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• Advances in single-cell biology have revolutionized the understanding of atherosclerosis, highlighting the interaction between different cell populations and molecular pathways in plaque progression and regression. • The formation and progression of atherosclerotic plaques are driven by LDL cholesterol and chronic exposure to pro-inflammatory stimuli, resulting in endothelial dysfunction and the formation of foam cells. • The concept of "vulnerable plaque" describes plaques prone to rupture, erosion, or calcified nodules, leading to acute coronary syndrome (ACS). Modern imaging techniques like IVUS, NIRS, and OCT are crucial for identifying and assessing these high-risk plaques. • Intensive lipid-lowering therapies, particularly statins and PCSK9 inhibitors, have shown efficacy in reducing plaque volume and stabilizing plaque features, with ongoing research needed to confirm their long-term benefits in reducing cardiovascular events. Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death globally despite advances in preventive therapies. Understanding of the initiation and progression of atherosclerosis, the interplay between lipoproteins, endothelial dysfunction, inflammation, and immune responses is critical to treating this disease. The development of vulnerable coronary plaques prone to thrombosis, can lead to acute coronary syndromes, for these reasons, the potential plaque stabilization and regression through pharmacological interventions, particularly lipid-lowering agents like statins and PCSK9 inhibitors is crucial. The imaging techniques such as intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT) play a key role in assessing plaque composition and guiding interventional therapeutic strategies. Clinical evidence supports the efficacy of intensive lipid-lowering therapy in inducing plaque regression, with studies demonstrating reductions in plaque volume and improvements in plaque morphology assessed by IVUS, OCT and NIRS. While pharmacological interventions show promise in promoting plaque regression and stabilization, their impact on long-term cardiovascular events requires further investigation. Multimodality imaging and comprehensive outcome trials are proposed as essential tools for elucidating the relationship between plaque modification and clinical benefit in coronary atherosclerosis. The stabilization or regression of atherosclerotic plaque might serve as the phenomenon linking the reduction in LDL-C levels to the decrease in cardiovascular events. Overall, this review emphasizes the ongoing efforts to advance our understanding of ASCVD pathophysiology and optimize therapeutic approaches for improving patient outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Radiation-induced pneumonitis (RIP) seriously limits the application of radiation therapy in the treatment of thoracic tumors, and its etiology and pathogenesis remain elusive. This study aimed to elucidate the role of ubiquitin-specific peptidase 11 (USP11) in the progression of RIP and the associated underlying mechanisms. Changes in cytokines and infiltrated immune cells were detected by enzyme-linked immunosorbent assays and immunohistochemistry after exposure to 20 Gy x-ray with whole-thorax irradiation. The effects of USP11 expression on endothelial cell proliferation and apoptosis were analyzed by costaining of CD31/Ki67 and CD31/caspase-3 in vivo, and the production of cytokines and reactive oxygen species was confirmed by reverse-transcription polymerase chain reaction and flow cytometry in vitro. Comprehensive proteome and ubiquitinome analyses were used for USP11 substrate screening after radiation. Results were verified by Western blotting and coimmunoprecipitation experiments. Recombinant adeno-associated virus lung vectors expressing OTUD5 were used for localized overexpression of OTUD5 in mouse pulmonary tissue, and immunohistochemistry was conducted to analyze cytokine expression. The progression of RIP was significantly alleviated by reduced expression of proinflammatory cytokines in both Usp11-knockout (Usp11−/−) mice and in mice treated with the USP11 inhibitor mitoxantrone. Likewise, the absence of USP11 resulted in decreased permeability of pulmonary vessels and neutrophils and macrophage infiltration. The proliferation rates of endothelial cells were prominently increased in the Usp11−/− lung, whereas apoptosis in Usp11−/− lungs decreased after irradiation compared with that observed in Usp11+/+ lungs. Conversely, USP11 overexpression increased proinflammatory cytokine expression and reactive oxygen species production in endothelial cells after radiation. Comprehensive proteome and ubiquitinome analyses indicated that USP11 overexpression upregulates the expression of several deubiquitinating enzymes, including USP22, USP33, and OTUD5. We demonstrate that USP11 deubiquitinates OTUD5 and implicates the OTUD5-STING signaling pathway in the progression of the inflammatory response in endothelial cells. USP11 exacerbates RIP by triggering an inflammatory response in endothelial cells both in vitro and in vivo, and the OTUD5-STING pathway is involved in the USP11-dependent promotion of RIP. This study provides experimental support for the development of precision intervention strategies targeting USP11 to mitigate RIP. [ABSTRACT FROM AUTHOR]

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo , as well as in atherosclerotic patients' arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1 , thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on Apoe KO Asf1a ECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis. Histone chaperone ASF1A and P300 together regulate histone H3 lysine 18 lactylation, which increases the expression of the endothelial-to-mesenchymal transition transcription factor SNAI1, inducing endothelial dysfunction and promoting atherosclerosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite impressive improvements in the care of patients with ST-segment elevation myocardial infarction, mortality remains high. Reperfusion is necessary for myocardial salvage, but the abrupt return of flow sets off a cascade of injurious processes that can lead to further necrosis. This has been termed myocardial ischemia-reperfusion injury and is the subject of this review. The pathologic and molecular bases for myocardial ischemia-reperfusion injury are increasingly understood and include injury from reactive oxygen species, inflammation, calcium overload, endothelial dysfunction, and impaired microvascular flow. A variety of pharmacologic strategies have been developed that have worked well in preclinical models and some have shown promise in the clinical setting. In addition, there are newer mechanical approaches including mechanical unloading of the heart prior to reperfusion that are in current clinical trials. [Display omitted] • MIRI exacerbates myocardial necrosis in patients with STEMI, contributing to mortality. • MIRI is mediated by varying combinations of ROS, inflammation, endothelial dysfunction, impaired microvascular flow, and other factors. • A variety of pharmacologic and mechanical strategies that mitigate MIRI in preclinical models have shown promise in clinical trials. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the antihypertensive and antioxidant effects of flaxseed oil in ouabain-induced hypertensive in normal rats Wistar. Experimental hypertension was induced by a daily subcutaneous (sc) injection of 10 μg/kg/day/rat of ouabain diluted in 9 g/L of saline solution (NaCl) for 21 days (n = 16). Animals were then divided into two groups fed an experimental diet containing 20% casein supplemented (Ouab-Oil- Lu) or not (Ouab) with 1% flaxseed oil whereas control rats (n = 8) received only a daily sc injection of NaCl. The results showed that supplementing hypertensive rats with 1% flaxseed oil decreased significantly (P < 0.05) the systolic, diastolic, and mean arterial pressure, ameliorated plasma and liver lipid profile and reduced glucose levels in plasma. Similarly, flaxseed oil decreased TBARS levels in plasma and tissues, as well as carbonyl levels in the heart. Interestingly, this supplementation increased GSH, thiols and nitric oxide levels and improved AchE and antioxidant enzyme activities (SOD and GSH-Px) in the tissues. Our findings suggested that flaxseed oil may provide a rationale for antihypertensive use in traditional medicine. [ABSTRACT FROM AUTHOR]

• A marker for inflammation was found in the blood of babies born to obese mothers. • Babies who became obese had a higher level of the inflammatory biomarker at birth. • Endocan may help us to understand inherited obesity through fetal programming. Numerous animal and epidemiologic studies have demonstrated a positive association between maternal obesity in pregnancy and obesity in offspring. The biologic mechanisms of this association remain under investigation. One proposed mechanism includes fetoplacental endothelial dysfunction secondary to inflammation. Endocan is a relatively new biomarker for endothelial dysfunction and inflammation. Our objectives were to examine (1) the association between maternal obesity and neonatal serum endocan at birth, and (2) the association between neonatal serum endocan at birth and pediatric obesity at 24–36 months of age. This was a secondary analysis of a prospective cohort of neonates born < 33 weeks gestation. Serum endocan was collected within 48 hours of birth. Serum endocan levels were compared in neonates born to obese mothers vs. those born to non-obese mothers. BMI data were retrospectively collected from cohort neonates between 24 and 36 months of age. The analysis included 120 mother/neonate dyads. Neonates born to obese mothers had higher median serum endocan at birth compared to neonates born to non-obese mothers (299 ng/L [205–586] vs. 251 ng/L [164–339], p = 0.045). In a linear regression modeled on neonatal serum endocan level, maternal obesity had a statistically significant positive association (p = 0.021). Higher mean serum endocan level at birth was associated with pediatric obesity between 24 and 36 months (obese vs. non-obese offspring; 574 ng/L (2 2 2) vs. 321 ng/L (1 6 6), p = 0.005). In our cohort of preterm neonates, elevated serum endocan at birth was associated with both maternal obesity and downstream pediatric obesity. More research is needed to understand intergenerational transmission of obesity. A large focus has been on epigenetic modification. Endothelial dysfunction and inflammation may play important roles in these pathways. Effective biomarkers, including endocan, may also serve as intermediate outcomes in future pregnancy research. [ABSTRACT FROM AUTHOR]

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors, and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression. Herein, we demonstrated that salvianic acid A (SAA) played a pivotal role in contributing to vascular normalization in the tumor-bearing mice, thereby improving delivery and effectiveness of the chemotherapeutic agent. SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells (HUVECs) exposed to hypoxia. Mechanistically, SAA was inclined to directly bind to the glycolytic enzyme PKM2, leading to a dramatic decrease in endothelial glycolysis. More importantly, SAA improved the endothelial integrity via activating the β -Catenin/Claudin-5 signaling axis in a PKM2-dependent manner. Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization. SAA alters endothelial glycolysis via binding to PKM2 and determines the fate of endothelial tight junctions by virtue of regulating β -Catenin/Claudin-5 axis cascade, thereby inciting tumor vascular normalization. [Display omitted] [ABSTRACT FROM AUTHOR]

The endothelialization of drug-eluting stents is delayed after implantation in patients with diabetes. Although numerous factors were implicated in hyperglycemia-induced endothelial dysfunction, the effects of stent drug coating degradation on endothelial dysfunction remains unclear. We hypothesized that diabetic conditions promote drugcoating degradation and enhance antiproliferative agent release, but that the rapid release of these antiproliferative agents inhibits endothelial cell proliferation leading to poor reendothelialization post-stenting. To verify this hypothesis, a dynamic hyperglycemic circulation system was introduced to measure the profile of drugcoating degradation in vitro. Flow cytometry and RNA sequencing were performed to evaluate endothelial cell proliferation. Moreover, a Type 1 diabetic rabbit model was generated and a rescue experiment conducted to evaluate the effects of rapid drugcoating elution on endothelial coverage in vivo. The main findings were as follows: 1) diabetic conditions promoted drugcoating degradation and increased antiproliferative agent release; 2) this increase in antiproliferative agent release inhibited endothelial cell proliferation and delayed endothelial coverage; and 3) strict glycemic control attenuated drugcoating degradation and promoted endothelial coverage post-stenting. This is the first study to illustrate rapid drugcoating degradation and its potential effects on endothelial recovery under diabetic conditions, highlighting the importance of strict glycemic management in patients with diabetes after drug-eluting stent implantation. Diabetic conditions promote drug coating degradation and increase the release of antiproliferative agents. Rapid drug coating degradation under diabetic conditions inhibits endothelial cell proliferation and delays endothelialization. Strict glycemic control attenuates drug coating degradation and promotes endothelialization. [Display omitted] [ABSTRACT FROM AUTHOR]

• Differential exosomal circRNAs and mRNAs expression profiles after PM 2.5 treatment. • ExoPM2.5 caused endothelial dysfunction by permeability and decreased relaxation. • hsa_circ_0012627, hsa_circ_0053261 and hsa_circ_0052810 may predict vascular injury. • Vascular stiffness caused by PM 2.5 may be partly due to exosomal circRNAs from lung. As an environmental pollutant, ambient fine particulate matter (PM 2.5) was linked to cardiovascular diseases. The molecular mechanisms underlying PM 2.5 -induced extrapulmonary disease has not been elucidated clearly. In this study the ambient PM 2.5 exposure mice model we established was to explore adverse effects of vessel and potential mechanisms. Long-term PM 2.5 exposure caused reduced lung function and vascular stiffness in mice. And chronic PM 2.5 induced migration and epithelial-mesenchymal transition (EMT) phenotype in BEAS-2B cells. After PM 2.5 treatment, the circRNAs and mRNAs levels of exosomes released by BEAS-2B cells were detected by competing endogenous RNA (ceRNA) array, which contained 1664 differentially expressed circRNAs (DE-circRNAs) and 308 differentially expressed mRNAs (DE-mRNAs). By bioinformatics analysis on host genes of DE-circRNAs, vascular diseases and some pathways related to vascular diseases including focal adhesion, tight junction and adherens junction were enriched. Then, ceRNA network was constructed, and DE-mRNAs in ceRNA network were conducted functional enrichment analysis by Ingenuity Pathway Analysis, which indicated that hsa_circ_0012627, hsa_circ_0053261 and hsa_circ_0052810 were related to vascular endothelial dysfunction. Furthermore, it was verified experimentally that ExoPM2.5 could induce endothelial dysfunction by increased endothelial permeability and decreased relaxation in vitro. In present study, we investigated in-depth knowledge into the molecule events related to PM 2.5 toxicity and pathogenesis of vascular diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Vascular endothelial dysfunction (ED) is one of the mechanisms underlying obesity-related hypertension. Perivascular adipose tissue (PVAT) surrounds blood vessels and influences the vascular endothelium function. Previous studies have demonstrated the antihypertensive effects of lactoferrin (LF) and its hydrolysates through various mechanisms. However, the effect of LF on ED and PVAT has not yet been investigated. In this study, we examined the influence of LF on ED and PVAT using high-fat diet mice as well as MAEC cells and 3T3-L1 adipocytes. Finally, LF supplementation decreases the systolic blood pressure (SBP), serum adhesion molecule (ICAM-1 and VCAM-1), and aorta ROS levels, and improves endothelium-dependent relaxation function in high-fat diet mice. Moreover, LF supplementation down-regulates the Tak1/IL-18/eNOS pathway between PVAT and aorta and enhances the NO generation in high-fat diet mice. In addition, we observe that LF decreases the expression levels of IL-18 and p-Tak1 in 3T3-L1 adipocytes, but fails to influence the eNOS and p-eNOS expression levels in MAEC cells. Finally, the significant associations between LF and IL-18 and SBP and hypertension risk are also observed in obesity children only. These findings provide evidence that the Tak1/IL-18/eNOS pathway between the aorta and PVAT is important in obesity-related ED, and LF may improve ED or even hypertension by down-regulating this pathway. [Display omitted] • LF improves the generation of NO and endothelium-dependent vasodilation in high-fat feed mice. • LF down-regulates the Tak1/IL-18/eNOS pathway between PVAT and aorta. • LF fails to increase the expression of p-eNOS and NO generation in MAEC cells. • LF inhibits the expression levels of p-Tak1 and IL-18 in 3T3-L1 adipocytes. • Serum LF level negatively associates with hypertension risk in obese children only. [ABSTRACT FROM AUTHOR]

Aim Although antiretroviral therapy (ART) is available, the rate of new HIV infections is alarming. With this trend, it is anticipated that the use of ART will continue to rise, potentially resulting in associated vascular disorders. Therefore, we aimed to examine the impact of ART on endothelial function in people living with HIV (PLHIV), a predictor of cardiovascular diseases. A comprehensive search for evidence was made on PubMed and Scopus on May 06, 2023, following the Preferred Reporting Items for Systematic Review and Meta-analysis. Cochrane and Newcastle–Ottawa quality assessment scales were used to evaluate quality, while the metaHun web tool and Review Manager version 5.4.1 were used for analysis. Subgroup, sensitivity, and publication bias were conducted for each outcome measure. We identified 37 studies, including a sample size of 3700 with 2265 individuals on ART. The analyzed evidence showed a large significant effect of ART on vascular cell adhesion molecule-1, with a standardized mean difference (SMD) of −1.23 (95 % CI: −1.72, −0.74; p = 0.0013). Similarly, a significant medium effect of ART was observed on intercellular cell adhesion molecule-1 in PLHIV, with an SMD of −1.28 (95 % CI: −2.00, −0.56; p = 0.0231) compared to the control group. Furthermore, ART exhibited a significant but small effect on flow-mediated dilation (FMD) with an SMD of −0.40 (95 % CI: −0.62, −0.19, p = 0.0159). Our findings show an improved endothelial function in PLHIV on ART, as demonstrated by reduced adhesion molecules; however, ART exhibited a small effect on FMD, thus suggesting PLHIV on ART may still be at risk of endothelial dysfunction and further cardiovascular diseases. [Display omitted] • People living with HIV on antiretroviral therapy (ART) have reduced cell adhesion molecules. • This ameliorates the risk of endothelial dysfunction in HIV. • The effect of ART on flow-mediated dilation is unclear in HIV. • This suggests a risk of endothelial dysfunction and associated cardiovascular disease. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. The tumor microenvironment (TME) contributes to the poor response of patients with HCC to current therapies, while tumor vascular endothelial cells (ECs) are fundamental TME components that significantly contribute to tumor progression. However, the specific functions and mechanisms of tumor vascular ECs in HCC remain unclear. We screened and validated diacylglycerol kinase gamma (DGKG) hyper-expression specifically in HCC tumor vascular ECs. Single-cell RNA-sequencing, cytometry by time-of-flight, and in vitro and in vivo studies were performed to investigate the functions of endothelial DGKG. Multiplexed immunohistochemistry staining and flow cytometry were used to evaluate changes in the TME. Functionally, endothelial DGKG promotes tumor angiogenesis and immunosuppressive regulatory T-cell differentiation in HCC. Of significance, we found that HIF-1α activates DGKG transcription by directly binding to its promoter region under hypoxia. Upregulated DGKG promotes HCC progression by recruiting ubiquitin specific peptidase 16 to facilitate ZEB2 deubiquitination, which increases TGF-β1 secretion, thus inducing tumor angiogenesis and regulatory T-cell differentiation. Importantly, targeting endothelial DGKG potentiated the efficiency of dual blockade of PD-1 and VEGFR-2. Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immune evasion via the ZEB2/TGF-β1 axis, suggesting EC-specific DGKG as a potential therapeutic target for HCC. Here, we reported that hypoxia-induced endothelial cell-specific DGKG hyper-expression promotes angiogenesis and immune evasion in HCC by recruiting USP16 for K48-linked deubiquitination and inducing the subsequent stabilization of ZEB2, leading to increased TGF-β1 secretion. Most importantly, endothelial DGKG inhibition greatly improved the efficacy of the dual combination of anti-VEGFR2 and anti-PD-1 treatment in a mouse HCC model, significantly inhibiting the malignant progression of HCC and improving survival. This preclinical study supports the targeting of endothelial DGKG as a potential strategy for precision HCC treatment. [Display omitted] • DGKG is hyper-expressed in HCC tumor vascular ECs and predicts poor survival. • Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immunosuppression. • DGKG recruits USP16 to facilitate ZEB2 deubiquitination, thus activating the TGF-β1 positive feedback loop. • Targeting endothelial DGKG enhances the efficacy of dual PD-1 and VEGFR-2 blockade. [ABSTRACT FROM AUTHOR]

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba , a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba , can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis. Ginkgolide B possesses the antiatherosclerotic advantage of "multitarget and multipathway", which is closely linked to its regulating endothelial dysfunction, thrombosis, leukocyte action, and risk factors. [Display omitted] [ABSTRACT FROM AUTHOR]

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)–PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF- κ B)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING–PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF- κ B via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING–PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF- κ B and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction. Non-canonical STING–PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction promotes atherosclerosis via integrating IRF3, NF- κ B and BRD4 in inflammatory response, which shed new light for atherosclerosis therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Oxidized LDL (oxLDL) and oxysterols are known to play a crucial role in endothelial dysfunction (ED) by inducing endoplasmic reticulum stress (ERS), inflammation, and apoptosis. However, the precise molecular mechanisms underlying these pathophysiological processes remain incompletely understood. Emerging evidence strongly implicates excessive nitric oxide (NO) production in the progression of various pathological conditions. The accumulation of reactive nitrogen species (RNS) leading to nitrosative stress (NSS) and aberrant protein S-nitrosylation contribute to NO toxicity. Studies have highlighted the involvement of NSS and S-nitrosylation in perturbing ER signaling through the modification of ER sensors and resident isomerases in neurons. This review focuses on the existing evidence that strongly associates NO with ERS and the possible implications in the context of ED induced by oxLDL and oxysterols. The potential effects of perturbed NO synthesis on signaling effectors linking NSS with ERS in endothelial cells are discussed to provide a conceptual framework for further investigations and the development of novel therapeutic strategies targeting ED. [Display omitted] • OxLDL and oxysterols induce endothelial dysfunction via unfolded protein response activation. • Nitrosative stress (NSS) and aberrant protein S-nitrosylation contribute to nitric oxide toxicity. • OxLDL and oxysterols promote eNOS uncoupling and iNOS induction leading to NSS. • Abnormal S-nitrosylation has been demonstrated in endothelial oxLDL-treated cells. • S-nitrosylation induces ER stress affecting ER sensors and isomerases activity. [ABSTRACT FROM AUTHOR]

• Extracellular vesicles cause a hypercoagulable state in patients with β-thalassemia. • Extracellular vesicles can increase iron overload in patients with β-thalassemia. • Microparticles cause inflammation and endothelial dysfunction in β-thalassemia. • Induction of apoptosis by extracellular vesicles contributes to organ disorders. Thalassemia is the most common monogenic disorder of red blood cells (RBCs) caused by defects in the synthesis of globin chains. Thalassemia phenotypes have a wide spectrum of clinical manifestations and vary from severe anemia requiring regular blood transfusions to clinically asymptomatic states. Ineffective erythropoiesis and toxicity caused by iron overload are major factors responsible for various complications in thalassemia patients, especially patients with β-thalassemia major (β-TM). Common complications in patients with thalassemia include iron overload, thrombosis, cardiac morbidity, vascular dysfunction, inflammation, and organ dysfunction. Extracellular vesicles (EVs) are small membrane vesicles released from various cells' plasma membranes due to activation and apoptosis. Based on studies, EVs play a role in various processes, including clot formation, vascular damage, and proinflammatory processes. In recent years, they have also been studied as biomarkers in the diagnosis and prognosis of diseases. Considering the high concentration of EVs in thalassemia and their role in cellular processes, this study reviews the role of EVs in the common complications of patients with β-thalassemia for the first time. [Display omitted] [ABSTRACT FROM AUTHOR]

Pulmonary embolism (PE) is a frequent complication in COVID19 hospitalized patients. Inflammatory storm and endothelial dysfunction due to the virus seem to be the two major risk factors for PE. Consequently, PE related to COVID19 could be consider as triggered by a transient inflammatory acute phase and treated for no longer than 3 months. However, few data are available on management of anticoagulation and risk of venous thromboembolic (VTE) recurrences in these patients and guidelines are still undefined. Aim of the present study is to evaluate the long-term follow-up of a cohort of covid-19 patients with PE. We conducted a retrospective multicenter study in four Italian hospitals between March 1st, 2020, and May 31st, 2021 in patients who experienced a PE during hospitalization for a COVID-19 pneumonia, excluding patients who died during hospitalization. Baseline characteristics were collected and patients were grouped according to duration of anticoagulant treatment (< 3 months or > 3 months). The primary outcome was incidence of VTE recurrence while secondary outcome was the composite of deaths, major hemorrhages and VTE recurrence during follow-up. 106 patients with PE were discharged, of these 95 (89.6 %) had follow up longer than 3 months (seven patients were lost to follow up and four died within three months). The median follow-up was 13 months (IQR 1–19). Overall, 23 % of subjects (22/95) were treated for 3 months or less and 76.8 % (73/95) received anticoagulation for >3 months. Of patients in the short treatment group, 4.5 % died, compared with 5.5 % of those in the longer treatment group (p = NS); no difference was shown in risk of VTE recurrence (0 % vs 4.1 %, p = NS), major bleeding (4.5 % vs 4.1 %, p = NS) or in composite outcome (9.1 % vs 11 %, p = NS). No difference was found between the two treatment groups for composite outcome using the Kaplan-Meier analysis (Log Rank Test p = 0.387). In our retrospective multi-center cohort, prolongation of duration of anticoagulation seems not to affect risk of VTE recurrences, deaths and bleeding after a PE related to COVID-19. • PE during hospitalization for COVID-19 seems to be provoked by SARS-COV2 infection. • 3 months of anticoagulation in these patients seem to be safe and efficacious. • Extended anticoagulation in these patients does not improve outcomes. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) significantly increased the incidence of coronary artery diseases, especially atherosclerosis. Endothelial dysfunction has been the major side effect of RT among tumor patients who received RT. However, the involvement between endothelial dysfunction and radiation-induced atherosclerosis (RIA) remains unclear. Here, we constructed a murine model of RIA, aiming to uncover its underlying mechanisms and identify novel strategies for RIA prevention and treatment. Eight-week-old ApoE−/− mice that were fed a Western diet were subjected to partial carotid ligation (PCL). Four weeks later, ionizing radiation (IR) of 10 Gy was performed to verify the detrimental role of IR on atherogenesis. Ultrasound imaging, RT quantitative polymerase chain reaction, histopathology and immunofluorescence, and biochemical analysis were performed 4 weeks after IR. To study the involvement of endothelial ferroptosis induced by IR in RIA, mice after IR were administrated with ferroptosis agonist (cisplatin) or antagonist (ferrostatin-1) intraperitoneally. Western blotting, autophagic flux measurement, reactive oxygen species level detection, and coimmunoprecipitation assay were carried out in vitro. Furthermore, to determine the effect of ferritinophagy inhibition on RIA, in vivo knockdown of NCOA4 was carried out by pluronic gel. We verified that accelerated plaque progression was concomitant with endothelial cell (EC) ferroptosis after IR induction, as suggested by a higher level of lipid peroxidation and changes in ferroptosis-associated genes in the PCL + IR group than in the PCL group within vasculature. In vitro experiments further validated the devastating effects of IR on oxidative stress and ferritinophagy in ECs. Mechanistic experiments revealed that IR induced EC ferritinophagy and subsequent ferroptosis in a P38/NCOA4-dependent manner. Both in vitro and in vivo experiments confirmed the therapeutic effect of NCOA4 knockdown in alleviating IR-induced ferritinophagy/ferroptosis of EC and RIA. Our findings provide novel insights into the regulatory mechanisms of RIA and first prove that IR accelerates atherosclerotic plaque progression by regulating ferritinophagy/ferroptosis of ECs in a P38/NCOA4-dependent manner. [ABSTRACT FROM AUTHOR]

Endocan is a proteoglycan secreted from endothelium upon endothelial damage. Since depression is associated with higher inflammation and oxidative stress to the vascular endothelium, endothelial dysfunction is prevalent and it is one of the responsible mechanisms for increased cardiovascular morbidity and mortality in depressive disorders. This study aimed to investigate endocan levels in patients with depression (either bipolar or unipolar) and healthy controls to evaluate the projected endothelial injury. We included nonsmoker patients without comorbid inflammatory conditions: 31 with Bipolar Disorder Depression (BDD), 30 with Major Depressive Disorder (MDD) and 25 healthy controls (HC). The severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS). Ultimately, serum endocan levels were significantly higher in patients with BDD than in patients with MDD (p <.000) and HCs (p <.000). Also, patients with MDD had significantly higher endocan levels than HCs (p <.000). The AUC value for the endocan to differentiate patients with depression from controls was 0.990 (95% CI: 0.971–1.000; p <.001) with sensitivity and specificity of 98.4 and 100%, respectively, and an optimal cut-off value of 316.92 ng/L. Serum endocan levels showed a mild positive correlation with HDRS scores (r = 0.372, p =.039) in the BDD group but not in the MDD group (r = −0.242, p =.20). Patients with BDD had higher endocan levels than MDD; this finding, while preliminary, could be an implication of higher endothelial dysfunction in BDD. [ABSTRACT FROM AUTHOR]

The complement system, particularly the alternative complement pathway, may contribute to vascular damage and development of cardiovascular disease (CVD). We investigated the association of factor D, the rate-limiting protease in alternative pathway activation, with adverse cardiovascular outcomes. In 2947 participants (50.6% men, 59.9 ± 8.2 years, 26.5% type 2 diabetes [T2D], oversampled) we measured markers of low-grade inflammation (LGI, composite score, in SD) and, endothelial dysfunction (ED, composite score, in SD), carotid intima-media thickness (cIMT, μm), ankle-brachial index (ABI), CVD (yes/no) and plasma concentrations of factor D (in SD). Associations were estimated using multiple linear and logistic regression, adjusting for demographic, lifestyle, and dietary factors. Factor D (per SD) significantly associated with LGI (0.171 SD [0.137; 0.205]), ED (0.158 SD [0.123; 0.194]) and CVD (OR 1.15 [1.04; 1.27]) but not significantly with cIMT (−6.62 μm [-13.51; 0.27]) or ABI (−0.003 [-0.007; 0.001]). Interaction analyses show that factor D more strongly associated with ED in non-diabetes (0.237 SD [0.189; 0.285] than in T2D (0.095 SD [0.034; 0.157]), p interaction <0.05. These results were largely corroborated by additional analyses with C3 and C3a. In contrast, factor D inversely associated with cIMT in non-diabetes (−13.37 μm [-21.84; −4.90]), but not in T2D (4.49 [-7.91; 16.89]), p interaction <0.05. Plasma factor D is independently associated with LGI, ED, and prevalent CVD but not with ABI or cIMT. Hence, greater plasma factor D concentration in CVD may potentially induce complement activation which, in turn, might contribute to further disease progression via a process that may involve inflammation and endothelial dysfunction but was not directly related to atherosclerosis or arterial injury. The observation that, in participants without diabetes, factor D associated with worse ED but smaller cIMT warrants further investigation. [Display omitted] • Greater plasma concentration of factor D significantly associates with multiple markers of low-grade inflammation and endothelial dysfunction. • Greater plasma concentration of factor D significantly associates with more cardiovascular disease. • These observations for factor D were largely corroborated in analyses with complement C3 and C3a. • The association of factor D with cardiovascular disease manifested particularly as cerebral cardiovascular disease in men. • Factor D was not positively associated with either a marker of subclinical atherosclerosis or a marker of arterial injury. [ABSTRACT FROM AUTHOR]

• A renewed interest exists in miRNAs as biomarkers in cardiovascular disease. • miR-126–3p is associated with albuminuria, a marker of endothelial dysfunction, in hypertension. • High miR-126–3p levels are associated with cardiovascular events in general population. Endothelial dysfunction is a forerunner of atherosclerosis, leading to cardiovascular disease, and albuminuria is a marker of endothelial dysfunction. Circulating levels of microRNAs are emerging as potential biomarkers for cardiovascular disease. Here we estimate the predictive value of a plasma microRNAs signature associated with albuminuria in the incidence of cardiovascular events. Plasma microRNAs quantified in hypertensive patients by next generation sequencing were validated in a cohort of patients and controls by real-time quantitative PCR. The microRNAs found to be associated with albuminuria were analysed for their prognostic value in predicting cardiovascular events incidence on a retrospective, population-based study (Hortega Study), using Cox proportional hazard models. A plasma microRNA profile was identified in the discovery cohort (n = 48) associated with albuminuria and three microRNAs (miR-126–3p, miR-1260b and miR-374a-5p) were confirmed in the validation cohort (n = 98). The microRNA signature discriminates urinary albumin excretion at baseline (n = 1025), and predicts the incidence of cardiovascular events and coronary heart disease and stroke in a general population retrospective study within a 14-year follow-up (n = 926). High miR-126–3p levels were associated with a shorter time free of both cardiovascular events (HR=1.48, (1.36–1.62), p < 0.0001), as well as coronary artery disease and stroke combined (HR=2.49, (2.19–2.83), p < 0.0001). An increased plasma microRNAs profile was identified in hypertensive patients with albuminuria. Increased miR-126–3p suggest it may serve as a prognostic marker for cardiovascular events in a long-term general population. Further studies will assess the potential role of miR-126–3p as a guide for the status of endothelial dysfunction. Circulating miR-126–3p as a prognostic marker of MACE and combined CAD and stroke in a long-term general population cohort. A signature of 4 miRNAs is associated with albuminuria in the discovery and validation cohorts of hypertensive patients and controls. in a general population cohort (Hortega testing cohort) followed during 14 years, increased levels of plasma circulating miR-126–3p are associated with the incidence of MACE (major adverse cardiovascular events) and combined CAD (coronary artery disease) and stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

Systemic endothelial dysfunction holds particular relevance in the context of preeclampsia because it has been associated with circulating placental factors, maternal major symptoms, and later cardiovascular risk. Studies profiling changes in preeclamptic maternal endothelial function have been explored for a long time but in vivo and in vitro models both have several limitations. Shear stress is a hemodynamic force that strongly regulates endothelial function and dysfunction. This biomechanical force is not considered by the majority of in vitro studies on this topic because they mostly utilize static endothelial cell cultures. The combination of advances in biotechnology and biomolecular approaches can improve our knowledge of the missing links between circulating biomarkers and maternal endothelial dysfunction in preeclampsia. This will provide a better understanding of its pathophysiology and lead to the identification of potential therapeutic targets. Preeclampsia, one of the main hypertensive disorders of pregnancy, is associated with circulating factors released by the ischemic placenta accompanied by systemic endothelial dysfunction. The etiology of preeclampsia remains poorly understood although it is associated with high maternal and fetal mortality and increased cardiovascular disease risk. Most cell model systems used for studying endothelial dysfunction have not taken into account hemodynamic physical factors such as shear-stress forces which may prevent extrapolation of cell data to in vivo settings. We overview the role of hemodynamic forces in modulating endothelial cell function and discuss strategies to reproduce this biological characteristic in vitro to improve our understanding of endothelial dysfunction associated with preeclampsia. [ABSTRACT FROM AUTHOR]

Studies investigating clinical outcomes of patients with or without endothelial disfunction (ED) treated with percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) using second generation drug eluting stents (DES) are lacking. We prospectively collected data from 109 patients undergoing PCI with second generation DES due to stable CAD between December 2014 and September 2016. ED was evaluated evaluating the flow mediated dilation (FMD) at the brachial artery level and defined by an FMD < 7 %. Primary outcome were major adverse cardiovascular events (MACE), secondary outcomes were target vessel failure (TVR), myocardial infarction (MI) and all-cause death. Five-year follow-up was available in all patients. Median FMD didn't significantly differ between patients who experienced the outcome and those who didn't [no TVR vs. TVR: p = 0.358; no MI vs. MI: p = 0.157; no death vs. death: p = 0.355; no MACE vs. MACE: p = 0.805]. No association between ED and an increased risk for the primary outcome as well as for the secondary ones was evident [MACE: 17.0 % vs. 14.3 %, HR 0.87 (0.33–2.26), log rank p = 0.780; TVR: 9.4 % vs. 5.4 %, HR 0.53 (0.12–2.24), log rank p = 0.384; MI: 3.7 % vs. 8.9 %, HR 2.46 (0.47–12.76), log rank p = 0.265; death: 7.5 % vs. 3.6 %, HR 0.53 (0.09–2.90), log rank p = 0.458]. These findings were confirmed using a lower threshold of FMD to define ED and at one-year landmark analysis. ED is not associated with an increased risk of adverse events at long-term follow-up in a contemporary cohort of patients undergoing PCI with second generation DES. • Patients with endothelial dysfunction (ED) have an increased risk of coronary artery disease • Previous studies on the association between ED and adverse events were limited by short follow-up and the use of bare metal or first generation drug-eluting stents (DES) • In patients treated with second generation DES, ED was not associated with adverse events at five years of follow-up [ABSTRACT FROM AUTHOR]

Despite extraordinary advances in the comprehension of the pathophysiology of atherosclerosis and the employment of very effective treatments, cardiovascular diseases are still a major cause of mortality and represent a large share of health expenditure worldwide. Atherosclerosis is a disease affecting the medium and large arteries, which consists of a progressive accumulation of fatty substances, cellular waste products and fibrous elements, which culminates in the buildup of a plaque obstructing the blood flow. Endothelial dysfunction represents an early pathological event, favoring immune cells recruitment and triggering local inflammation. The release of inflammatory cytokines and other signaling molecules stimulates phenotypic modifications in the underlying vascular smooth muscle cells, which, in physiological conditions, are responsible for the maintenance of vessels architecture while regulating vascular tone. Vascular smooth muscle cells are highly plastic and may respond to disease stimuli by de-differentiating and losing their contractility, while increasing their synthetic, proliferative, and migratory capacity. This phenotypic switching is considered a pathological hallmark of atherogenesis and is ruled by the activation of selective gene programs. The advent of genomics and the improvement of sequencing technologies deepened our knowledge of the complex gene expression regulatory networks mediated by non-coding RNAs, and favored the rise of innovative therapeutic approaches targeting the non-coding transcriptome. In the context of atherosclerosis, long non-coding RNAs have received increasing attention as potential translational targets, due to their contribution to the molecular dynamics modulating the expression of vascular smooth muscle cells contractile/synthetic gene programs. In this review, we will focus on the most well-characterized long non-coding RNAs contributing to atherosclerosis by controlling expression of the contractile apparatus and genes activated in perturbed vascular smooth muscle cells. [Display omitted] • Vascular smooth muscle cells (VSMCs) are highly plastic cells responsible for vessel architecture and contractility. • VSMCs switch to a synthetic and hyperproliferative phenotype is a major hallmark of atherogenesis and plaques buildup. • Long non-coding RNAs (lncRNAs) are major contributors of VSMCs phenotypic modulation. • LncRNAs may serve as therapeutic targets in atherosclerosis and biomarkers for plaque stability. [ABSTRACT FROM AUTHOR]

Fluid retention and endothelial dysfunction have been related to use of nonsteroidal anti-inflammatory drugs (NSAIDs), and type 2 diabetes mellitus (T2DM) has been linked to both a decline in kidney function and subclinical cardiomyopathy. The authors hypothesized that short-term use of NSAIDs could lead to subsequent development of incident heart failure (HF) in patients with T2DM. Using nationwide Danish registers, we identified patients diagnosed with T2DM during 1998 to 2021 and included patients without previous HF, rheumatic disease, or use of NSAIDs 120 days before diagnosis. Associations between NSAIDs and first-time HF hospitalization were investigated using a case-crossover design with 28-day exposure windows, and ORs with 95% CIs were reported. Included were 331,189 patients with T2DM: 44.2% female, median age of 62 years (IQR: 52-71 years); 23,308 patients were hospitalized with HF during follow-up, and 16% of patients claimed at least 1 NSAID prescription within 1 year. Short-term use of NSAIDs was associated with increased risk of HF hospitalization (OR: 1.43; 95% CI: 1.27-1.63), most notably in subgroups with age ≥80 years (OR: 1.78; 95% CI: 1.39-2.28), elevated hemoglobin (Hb) A1c levels treated with 0 to 1 antidiabetic drug (OR: 1.68; 95% CI: 1.00-2.88), and without previous use of NSAIDs (OR: 2.71; 95% CI: 1.78-4.23). NSAIDs were widely used and were associated with an increased risk of first-time HF hospitalization in patients with T2DM. Patients with advanced age, elevated HbA1c levels, and new users of NSAID seemed more susceptible. These findings could guide physicians prescribing NSAIDs. [Display omitted] [ABSTRACT FROM AUTHOR]

Recently, there has been increasing awareness that bleeding may lead to adverse outcomes. Endothelial dysfunction is associated with increased risk of cardiovascular and bleeding events. This study aimed to investigate the association of endothelial dysfunction with major bleeding and specific causes of death in addition to major adverse cardiovascular events in patients with acute coronary syndrome. This single-centre retrospective observational study was conducted at a tertiary-care hospital; patients with acute coronary syndrome were included between June 2010 and November 2014 (median follow-up, 6.1 years). The reactive hyperaemia index was assessed before their discharge; reactive hyperaemia index <1.67 was defined as endothelial dysfunction. The main outcomes were the incidence of major bleeding, all-cause death, cardiovascular death, non-cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. Among the included 674 patients with acute coronary syndrome, 264 (39.2%) had endothelial dysfunction. Multivariable Cox-hazard analyses revealed an independent predictive value of endothelial dysfunction for major bleeding (hazard ratio 2.29, 95% confidence interval 1.17–4.48, P = 0.016) and major adverse cardiovascular events (hazard ratio 2.04, 95% confidence interval 1.43–2.89, P < 0.001). The endothelial dysfunction group patients had a 2.5-fold greater risk of cardiovascular death; however, no association was found with non-cardiovascular death. Endothelial dysfunction assessed using reactive hyperaemia index predicted future major cardiovascular event as well as major bleeding and cardiovascular death in patients with acute coronary syndrome. [Display omitted] • Endothelial dysfunction (ED) was related to 2.5-fold higher cardiovascular mortality. • ED was associated with not only atherothrombotic but also bleeding events. • ED could be a comprehensive marker of vascular health. [ABSTRACT FROM AUTHOR]

METRNL is a recently identified secreted protein with emerging functions. This study is to find major cellular source of circulating METRNL and to determine METRNL novel function. Here, we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway. By creating endothelial cell-specific Metrnl knockout mice, combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl , we demonstrate that most of circulating METRNL (approximately 75%) originates from the endothelial cells. Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients. By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice, combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice, we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis. Mechanically, endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NF κ B pathway, which promotes the susceptibility of atherosclerosis. Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction. These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease. METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis. This study reveals that METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Preeclampsia is a multisystemic condition causing severe implications in mothers and children suffering from proteinuria and gestational hypertension. Globally, there is an upsurge in morbidity and mortality due to preeclampsia and its complications such as hypertension, endothelial dysfunction, various cardiovascular diseases and proteinuria. Research and meta-analysis on preeclampsia are emphasized as complete understanding about its underlying cause remains to be obscure. The occurrence of preeclampsia is indicated by the presence of elevated levels of methylenetetrahydrofolate reductase (MTHFR), homocysteine and asymmetric dimethylarginine (ADMA) which are well known to be associated with risk factors and are therefore considered as prognostic biomarkers for identifying women with preeclampsia at a very early stage. Elevated levels of these biomarkers cause chronic inflammation which impairs endothelial function. Endothelial dysfunction has been notably prominent in studies addressing the complications of preeclampsia such as cardiovascular disease (CVD). Various analytical techniques have been employed in the accurate screening and quantification of these molecules which is crucial in understanding molecular mechanisms underlying the pathophysiology of various preeclamptic complications. The epigenetic modifications in certain genes not only alter the biosynthesis and regulation of MTHFR, homocysteine and ADMA but also act as individual markers leading to conditions that heighten preeclampsia, giving rise to cardiovascular risk during and after preeclampsia. Therefore, multiple biomarkers are often desired because of their synergistic effect to enhance clinical efficiency. This review focuses on the metabolic links between MTHFR, homocysteine and ADMA, their role as preeclampsia risk predictors, their lowering mechanisms, strategies that incorporate multiple markers and their importance over individualistic biomarkers. In conclusion, the use of a multiple biomarker approach with MTHFR SNPs, homocysteine and ADMA can contribute to the advanced prediction of preeclampsia and its complications. • Preeclampsia-multisystemic condition with severe implications in mother and child. • Research on preeclampsia is emphasized that understanding remains to be obscure. • Preeclampsia is by the presence of elevated levels of MTHFR, homocysteine and ADMA. • Elevation of these biomarkers cause chronic inflammation & endothelial malfunction. • This systematic review provides insights on the above scenario and their relations. [ABSTRACT FROM AUTHOR]

Circulating fatty acid-binding protein 3 (FABP3) is an effective biomarker of myocardial injury and peripheral artery disease (PAD). The endothelium, which forms the inner most layer of every blood vessel, is exposed to higher levels of FABP3 in PAD or following myocardial injury, but the pathophysiological role of endothelial FABP3, the effect of FABP3 exposure on endothelial cells, and related mechanisms are unknown. Here, we aimed to evaluate the pathophysiological role of endothelial FABP3 and related mechanisms in vitro. Our molecular and functional in vitro analyses show that (1) FABP3 is basally expressed in endothelial cells; (2) inflammatory stress in the form of lipopolysaccharide (LPS) upregulated endothelial FABP3 expression; (3) loss of endogenous FABP3 protected endothelial cells against LPS-induced endothelial dysfunction; however, exogenous FABP3 exposure exacerbated LPS-induced inflammation; (4) loss of endogenous FABP3 protected against LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling pathways. Together, these findings suggest that gain-of endothelial FABP3 exacerbates, whereas loss-of endothelial FABP3 inhibits LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling. We propose that an increased circulating FABP3 in myocardial injury or PAD patients may be detrimental to endothelial function, and therefore, therapies aimed at inhibiting FABP3 may improve endothelial function in diseased states. [ABSTRACT FROM AUTHOR]

• Postocclusive reactive hyperemia (PORH) is a noninvasive test for microcirculation. • Endothelial function can be measured by PORH using laser Doppler flowmetry. • The hormonal milieu affects microvascular function during ovarian stimulation. • Blunting PORH indicates an early endothelial dysfunction in normoandrogenemic PCOS. Is there an association between post-occlusive reactive hyperaemia (PORH) and ovarian stimulation in women with normoandrogenaemic polycystic ovary syndrome (PCOS)? Women eligible for IVF at an academic fertility centre were invited to join this prospective study. Microvascular endothelial function was measured as PORH by laser Doppler flowmetry (LDF) before and after ovarian stimulation. Metabolic characteristics, hormone profiles and biochemical markers were analysed. Thirty-four normoandrogenaemic women with PCOS and 36 normoandrogenaemic women without PCOS were included. The PCOS group displayed higher C-reactive protein levels and insulin resistance (P = 0.048 and P = 0.025, respectively). No significant difference was found in microcirculatory function between the groups at baseline. After ovarian stimulation, PORH was enhanced in the control group (slope 7.1 ± 3.3 versus 9.7 ± 4.5; P = 0.007; peak flow 30.7 ± 16.3 versus 43.5 ± 17.3, P = 0.008; however, the PCOS group experienced a blunting response to supraphysiological hormone status (slope 8.2 ± 5.1 versus 7.2 ± 4.3, P = 0.212; peak flow, 38.8 ± 19.4 versus 37.0 ± 21.8, P = 0.895). Impaired microcirculatory function could be found using a non-invasive LDF technique in normoandrogenaemic women with PCOS undergoing IVF, indicating early changes in vascular endothelial dysfunction. Future observational studies should clarify whether PORH measurement might help predict IVF prognosis or obstetric complications. [ABSTRACT FROM AUTHOR]

Cardiac injury and inflammation are common findings in COVID-19 patients. Autopsy studies have revealed cardiac microvascular endothelial damage and thrombosis in COVID-19 patients, indicative of microvascular dysfunction in which reactive oxygen species (ROS) may play a role. We explored whether the ROS producing proteins NOX2, NOX4 and NOX5 are involved in COVID-19-induced cardio-microvascular endothelial dysfunction. Heart tissue were taken from the left (LV) and right (RV) ventricle of COVID-19 patients (n = 15) and the LV of controls (n = 14) at autopsy. The NOX2-, NOX4-, NOX5- and Nitrotyrosine (NT)-positive intramyocardial blood vessels fractions were quantitatively analyzed using immunohistochemistry. The LV NOX2+, NOX5+ and NT+ blood vessels fractions in COVID-19 patients were significantly higher than in controls. The fraction of NOX4+ blood vessels in COVID-19 patients was comparable with controls. In COVID-19 patients, the fractions of NOX2+, NOX5+ and NT+ vessels did not differ significantly between the LV and RV, and correlated positively between LV and RV in case of NOX5 (r = 0.710; p = 0.006). A negative correlation between NOX5 and NOX2 (r = −0.591; p = 0.029) and between NOX5 and disease time (r = −0.576; p = 0.034) was noted in the LV of COVID-19 patients. We show the induction of NOX2 and NOX5 in the cardiac microvascular endothelium in COVID-19 patients, which may contribute to the previously observed cardio-microvascular dysfunction in COVID-19 patients. The exact roles of these NOXes in pathogenesis of COVID-19 however remain to be elucidated. • The ROS producing proteins NOX2 and NOX5 are increased in COVID-19 patients. • For the first time NOX proteins were analyzed in the hearts of COVID-19 patients. • Oxidative stress plays a role in COVID-19-induced cardiac microvascular dysfunction. • These inducible NOX proteins may provide a potential target for therapy. [ABSTRACT FROM AUTHOR]

Coronary endothelial dysfunction and vasospasm are potential causes of ischemia in patients without obstructive coronary stenoses (INOCA). To evaluate the prevalence of endothelial dysfunction and the clinical profile of patients with INOCA in Spain, as well as to identify the predictors and the prognostic impact of endothelial dysfunction in this scenario. A total of 438 consecutive patients with INOCA in whom the acetylcholine test was performed were prospectively enrolled. Patients were followed up at 1 and 2 years. Mean age was 62 ± 11 years with 60% female. Clinical presentation comprised 52.6% angina at rest, 61.2% exertional angina, and 31.7% dyspnea. There were no major complications of the acetylcholine test. Endothelial dysfunction was observed in 198 (45%) of patients, with severe vasoconstriction (defined as over 70% constriction), being observed in 101 (23%). Multivariable regression analysis showed that endothelial dysfunction was predicted by the presence of exertional angina (OR 2.2; CI95%1.01–2.55; p = 0.02), prior coronary disease (OR 2.46; CI95% 1.57–3.89; p < 0.01), and coronary intramyocardial bridging (2.35; CI95% 1.02–5.60; p = 0.04). Patients with endothelial dysfunction presented with worsening angina compared to those without endothelial dysfunction (25.6% vs. 12.8%) and also presented with increased levels of minimal effort angina (40% vs. 26,7%, p = 0.03) more frequently during the follow up than those without endothelial dysfunction. Endothelial dysfunction was also an independent predictor of the occurrence of myocardial infarction or unstable angina at one year (OR 2.85, CI 95% 1.01–9.25; p = 0.03). Endothelial dysfunction is present in almost half of patients with INOCA and is associated with worsening symptoms, as well as with a higher rate of adverse events. [Display omitted] • Almost half of patients with INOCA have coronary endothelial dysfunction. • Exertional angina is a predictor of coronary endothelial dysfunction in INOCA. • Coronary endothelial dysfunction is a predictor of cardiovascular events in patients with INOCA. [ABSTRACT FROM AUTHOR]

Ambient air pollution is recognised globally as a significant contributor to the burden of cardiovascular diseases. The evidence from both human and animal studies supporting the cardiovascular impact of exposure to air pollution has grown substantially, implicating numerous pathophysiological pathways and related signalling mediators. In this review, we summarise the list of activated mediators for each pathway that lead to myocardial and vascular injury in response to air pollutants. We performed a systematic search of multiple databases, including articles between 1990 and Jan 2022, summarising the evidence for activated pathways in response to each significant air pollutant. Particulate matter <2.5 μm (PM 2.5) was the most studied pollutant, followed by particulate matter between 2.5 μm–10 μm (PM 10), nitrogen dioxide (NO 2) and ozone (O 3). Key pathogenic pathways that emerged included activation of systemic and local inflammation, oxidative stress, endothelial dysfunction, and autonomic dysfunction. We looked at how potential mediators of each of these pathways were linked to both cardiovascular disease and air pollution and included the overlapping mediators. This review illustrates the complex relationship between air pollution and cardiovascular diseases, and discusses challenges in moving beyond associations, towards understanding causal contributions of specific pathways and markers that may inform us regarding an individual's exposure, response, and likely risk. [ABSTRACT FROM AUTHOR]

Hyperlipidemia-associated cytokines and disturbed flow upregulate SOX4 expression in ECs, where SOX4 promotes EndoMT and atherogenesis. Metformin pharmacologically suppresses SOX4 level in ECs. EC, endothelial cell; IL-1β, interleukin-1β; TGF-β1, transforming growth factor β1. [Display omitted] • Hyperlipidemia enriched mesenchymal markers in EC cluster of atherosclerotic mice. • EC cluster can be partitioned into ' endothelial-like ' and ' mesenchymal-like ' subpopulations. • SOX4 was upregulated in mouse and human atherosclerotic tissues. • SOX4 upregulation was observed in human aneurysmal tissues. • EC-specific SOX4 overexpression promoted EndoMT, endothelial dysfunction and atherogenesis. • Hyperlipidemia-related cytokines and disturbed flow upregulated endothelial SOX4 level. Atherosclerotic complications represent the leading cause of cardiovascular mortality globally. Dysfunction of endothelial cells (ECs) often initiates the pathological events in atherosclerosis. In this study, we sought to investigate the transcriptional profile of atherosclerotic aortae, identify novel regulator in dysfunctional ECs and hence provide mechanistic insights into atherosclerotic progression. We applied single-cell RNA sequencing (scRNA-seq) on aortic cells from Western diet-fed apolipoprotein E-deficient (ApoE−/−) mice to explore the transcriptional landscape and heterogeneity of dysfunctional ECs. In vivo validation of SOX4 upregulation in ECs were performed in atherosclerotic tissues, including mouse aortic tissues, human coronary arteries, and human renal arteries. Single-cell analysis on human aortic aneurysmal tissue was also performed. Downstream vascular abnormalities induced by EC-specific SOX4 overexpression, and upstream modulators of SOX4 were revealed by biochemical assays, immunostaining, and wire myography. Effects of shear stress on endothelial SOX4 expression was investigated by in vitro hemodynamic study. Among the compendium of aortic cells, mesenchymal markers in ECs were significantly enriched. Two EC subsets were subsequently distinguished, as the ' endothelial-like ' and ' mesenchymal-like ' subsets. Conventional assays consistently identified SOX4 as a novel atherosclerotic marker in mouse and different human arteries, additional to a cancer marker. EC-specific SOX4 overexpression promoted atherogenesis and endothelial-to-mesenchymal transition (EndoMT). Importantly, hyperlipidemia-associated cytokines and oscillatory blood flow upregulated, whereas the anti-diabetic drug metformin pharmacologically suppressed SOX4 level in ECs. Our study unravels SOX4 as a novel phenotypic regulator during endothelial dysfunction, which exacerbates atherogenesis. Our study also pinpoints hyperlipidemia-associated cytokines and oscillatory blood flow as endogenous SOX4 inducers, providing more therapeutic insights against atherosclerotic diseases. [ABSTRACT FROM AUTHOR]

Diabetes is associated with vascular injury and the onset of macrovascular complications. Advanced glycation endproducts (AGEs) and the AGE precursor methylglyoxal (MGO) have been identified as key players in establishing the relationship between diabetes and vascular injury. While most research has focused on the link between AGEs and vascular injury, less is known about the effects of MGO on vasculature. In this review, we focus on the mechanisms linking AGEs and MGO to the development of atherosclerosis. AGEs and MGO are involved in many stages of atherosclerosis progression. However, more research is needed to determine the exact mechanisms underlying these effects. Nevertheless, AGEs and MGO could represent valid therapeutic targets for the macrovascular complications of diabetes. The reactive dicarbonyl methylglyoxal (MGO) is the major precursor of endogenously formed advanced glycation endproducts (AGEs). MGO is an important factor contributing to endothelial dysfunction by inducing oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress. AGEs stimulate cholesterol accumulation in macrophages and phenotype switching of vascular smooth muscle cells (VSMCs) into macrophage-like cells, while the impact of MGO is less understood. AGEs and MGO can inhibit angiogenesis, but promote atherosclerosis-linked inflammation by inducing inflammatory polarization of macrophages and the induction of inflammatory pathways. AGEs promote calcification of VSMCs by increasing the expression of osteogenic proteins and transcription factors. The impact of MGO on calcification remains to be elucidated. [ABSTRACT FROM AUTHOR]

Myocardial ischemia with no obstructive coronary arteries (INOCA) is a chronic coronary syndrome condition that is increasingly being recognized as a substantial contributor to adverse cardiovascular mortality and outcomes, including myocardial infarction and heart failure with preserved ejection fraction (HFpEF). While INOCA occurs in both women and men, women are more likely to have the finding of INOCA and are more adversely impacted by angina, with recurrent hospitalizations and a lower quality of life with this condition. Abnormal epicardial coronary vascular function and coronary microvascular dysfunction (CMD) have been identified in a majority of INOCA patients on invasive coronary function testing. CMD can co-exist with obstructive epicardial coronary artery disease (CAD), diffuse non-obstructive epicardial CAD, and with coronary vasospasm. Epicardial vasospasm can also occur with normal coronary arteries that have no atherosclerotic plaque on intravascular imaging. While all predisposing factors are not clearly understood, cardiometabolic risk factors, and endothelium dependent and independent mechanisms that increase oxidative stress and inflammation are associated with microvascular injury, CMD and INOCA. Cardiac autonomic dysfunction has also been implicated in abnormal vasoreactivity and persistent symptoms. INOCA is under-recognized and under-diagnosed, partly due to the heterogenous patient populations and mechanisms. However, diagnostic testing methods are available to guide INOCA management. Treatment of INOCA is evolving, and focuses on cardiac risk factor control, improving ischemia, reducing atherosclerosis progression, and improving angina and quality of life. This review focuses on INOCA, relations to HFpEF, available diagnostics, current and investigational therapeutic strategies, and knowledge gaps in this condition. [Display omitted] • INOCA is associated with adverse cardiovascular mortality and outcomes, including myocardial infarction and heart failure. • INOCA portends an adverse prognosis in both sexes. Women are more impacted by angina, recurrent hospitalizations, and a lower quality of life. • In addition to diffuse atherosclerosis and endothelial dysfunction, CMD is implicated in INOCA. Vasospasm can also occur without visible plaque. • Invasive coronary function testing assesses abnormal epicardial and microcirculatory dysfunction as well as vasospasm. • Treatment includes anti-anginal/anti-ischemic and non-pharmacologic strategies, while outcomes-based trials are ongoing. [ABSTRACT FROM AUTHOR]

Endotoxins carried within LDL are cleared from the circulation via hepatic LDL receptor (LDLR)-mediated endocytosis. Proprotein convertase subtilisin-kexin type 9 (PCSK9) reduces this clearance by down-regulating LDLR density on hepatocytes. In addition to hepatocytes, vascular endothelial cells also express receptor targets of PCSK9, including LDLR. Therefore, we hypothesized that PCSK9 may regulate vascular endothelial cell uptake of lipopolysaccharide (LPS) and alter the vascular endothelial cell inflammatory response. We found that LPS is internalized by human umbilical vein vascular endothelial cells (HUVECs) and LPS uptake dose-dependently increased with increasing LDL concentration. Intracellular LPS co-localized with LDL. PCSK9 and, separately, blocking antibodies against LDLR, dose-dependently decreased the vascular endothelial cell uptake of LPS and, furthermore, inhibition of endocytosis using Dynasore blocked LPS uptake. In contrast, blocking antibodies against TLR4 did not alter LPS uptake. PCSK9 decreased the LPS-induced proinflammatory response (IL-6 and IL-8 gene expression and protein secretion, and VCAM-1/ICAM-1 expression) in vascular endothelial cells. In addition, a decrease in PCSK9 and increase in LDLR, mediated by triciribine or siPCSK9, increased LPS uptake and the LPS-induced proinflammatory response. Similar results were also found in aortic vascular tissue from Pcsk9 −/− mice after LPS injection. Our data suggest that, similar to PCSK9 treatment in hepatocytes, PCSK9 reduces vascular endothelial cell uptake of LPS via LDLR-mediated endocytosis. Consequently, PCSK9 decreases the LPS-induced proinflammatory response in vascular endothelial cells. These results raise the possibility that PCSK9 inhibition may have additional effects on vascular endothelial inflammation via this alternative pathway, beyond the known effects of PCSK9 inhibition on LDL lowering and hepatic endotoxin clearance. [Display omitted] • Lipopolysaccharide (LPS) uptake in HUVECs is dose-dependent on LDL concentration. • PCSK9 dose-dependently inhibits LDLR-mediated endocytosis of LPS in HUVECs. • Decreased PCSK9 increases endothelial cell LPS uptake and proinflammatory response. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome is a syndrome of acute heart failure due to left ventricular systolic dysfunction that is associated with increased cardiovascular morbidity and mortality. It occurs in both sexes and at all ages, but predominates in post-menopausal women for reasons that are unclear. In a patient who presents with cardiac symptoms, electrocardiographic changes, and/or biomarker elevation indicating myocardial stress (i.e. troponin elevation), this condition should be considered in the differential diagnosis. Cardiac imaging is critical for a timely diagnosis of this condition and has management implications. This syndrome can occur with or without underlying coronary artery disease, and while there are various characteristic myocardial patterns described on imaging, the most common one is left ventricular dysfunction due to apical stunning with basal hyperkinesis. In the acute phase, Takotsubo syndrome can lead to life-threatening sequelae, including cardiogenic shock, pulmonary edema, thromboembolism, and arrhythmias. Multiple pathophysiologic mechanisms are implicated, including an acute increase in left ventricular afterload in the setting of sympathetic activation with a catecholamine storm, multi-vessel coronary vasospasm, coronary endothelial microvascular dysfunction, and inflammation. In this review, we discuss the current knowledge surrounding presentation, diagnosis, and treatment of this under-diagnosed condition. [ABSTRACT FROM AUTHOR]

• Cardiac endothelial α 1 -AR activation inhibits cardiac dysfunction of septic mice. • Cardiac endothelial α 1 -AR activation inhibits endothelial injuries of septic mice. • The inhibition of endothelial injuries was via PKC-ERK/p38MAPK pathway. Cardiomyopathy is particularly common in septic patients. Our previous studies have shown that activation of the alpha 1 adrenergic receptor (α 1 -AR) on cardiomyocytes inhibits sepsis-induced myocardial dysfunction. However, the role of cardiac endothelial α 1 -AR in septic cardiomyopathy has not been determined. Here, we identified α 1 -AR expression in mouse and human endothelial cells and showed that activation of α 1 -AR with phenylephrine (PE) improved cardiac function and survival by preventing cardiac endothelial injury in septic mice. Mechanistically, activating α 1 -AR with PE decreased the expression of ICAM-1, VCAM-1, iNOS, E-selectin, and p-p38MAPK, while promoting PKC and ERK1/2 phosphorylation in LPS-treated endothelial cells. These effects were abolished by a PKC inhibitor or α 1 -AR antagonist. PE also reduced p65 nuclear translocation, but this suppression is not blocked by PKC inhibition. Treatment with U0126 (a specific ERK1/2 inhibitor) reversed the effects of PE on p38MAPK phosphorylation. Our results demonstrate that cardiac endothelial α 1 -AR activation prevents sepsis-induced myocardial dysfunction in mice by inhibiting the endothelial injury via PKC-ERK/p38MAPK signaling pathway and a PKC-independent inhibition of p65 nuclear translocation. These findings offer a new perspective for septic patients with cardiac dysfunction by inhibiting cardiac endothelial cell injury through α 1 -AR activation. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD), represents a growing health concern due to its strong association with metabolic syndrome, obesity, and type 2 diabetes mellitus (T2DM). This condition, characterized by excessive fat accumulation in the liver not attributed to alcohol consumption, has emerged as a leading cause of chronic liver disease globally. MASLD significantly elevates the risk of major adverse cardiovascular events (MACE) through mechanisms like increased oxidative stress, insulin resistance, and chronic inflammation, all of which contribute to the development of atherosclerosis and endothelial dysfunction. Effective management of MASLD is crucial not only for liver health but also for cardiovascular disease (CVD) prevention. Lifestyle modifications, particularly weight loss achieved through dietary changes and increased physical activity, are the cornerstone of MASLD treatment. Additionally, pharmacological interventions, especially antihyperglycemic agents, play a pivotal role in treating MASLD in patients with T2DM. Novel therapeutic agents targeting various pathways of metabolic and liver dysfunction are under investigation, offering hope for more effective management strategies. This review explores the interconnectedness of MASLD and CVD, highlighting current and emerging therapeutic approaches. [ABSTRACT FROM AUTHOR]

Flavivirus infections result in a variety of outcomes, from clinically inapparent infections to severe, sometimes fatal cases characterized by hemorrhagic manifestations and vascular leakage leading to shock (dengue), meningomyeloencephalitis (West Nile), and congenital abnormalities (Zika). Although there are approved vaccines against several flaviviruses, potentially enhancing cross-reactive immune responses have complicated the development and implementation of vaccines against dengue and Zika viruses, and no specific therapeutics currently exist. The flavivirus nonstructural protein 1 (NS1) is a promising antiviral target because it is a conserved multifunctional virulence factor that directly triggers vascular leak. We previously showed that interactions between NS1 and the ApoA1 lipoprotein modulate DENV infection. Here, we evaluated the potential of the ApoA1-mimetic peptide, 4F, to interfere with endothelial dysfunction mediated by the NS1 protein of dengue, Zika, and West Nile flaviviruses. In an in vitro model consisting of human endothelial cell monolayers, 4F inhibited NS1-induced hyperpermeability, as measured by a transendothelial electrical resistance assay, and prevented NS1-triggered disruption of the endothelial glycocalyx layer. We also demonstrate that treatment with 4F inhibited NS1 interaction with endothelial cells. Finally, we show that 4F protects against lethal DENV challenge in a mouse model, reducing morbidity and mortality in a dose-dependent manner. Our data demonstrate the potential of 4F to inhibit flavivirus NS1-mediated pathology and severe dengue disease in mice and suggest that 4F can also serve as a molecular tool to probe different NS1 functions in vitro and in vivo. • ApoA1-mimetic 4F inhibits flavivirus NS1 internalization into endothelial cells and NS1-induced endothelial dysfunction. • In vivo 4F treatment robustly reduces morbidity and protects against lethal challenge in a mouse model of dengue disease. • 4F exhibits potential to serve as a novel therapeutic to inhibit flavivirus NS1-mediated pathogenesis and dengue disease. [ABSTRACT FROM AUTHOR]

Preeclampsia is a complex and serious pregnancy disorder that leads to maternal and neonatal mortality worldwide. Kefir peptides (KPs), derived from various prebiotic fermentations in whole milk by kefir grains, were investigated for their potential therapeutic effects. In this study, we used the L-NAME in drinking water to induce a preeclampsia-like condition in spontaneous hypertension stroke-prone (SHRSP) pregnant rats. The rats were assigned to five groups: the normal group (WKY rats), the untreated group (SHRSP rat control pregnant), the L-NAME/Mock group (SHRSP rats fed with L-NAME water), the L-NAME/KPs-LD group (SHRSP rats fed with L-NAME water and low-dose KPs diets), and the L-NAME/KPs-HD group (SHRSP rats fed with L-NAME water and high-dose KPs diets) for a 20-day experiment. Chorioallantois membrane (CAM) assay was applied for ex vivo angiogenesis study of KPs treatment. Data showed that rats in the L-NAME group developed severe hypertension, proteinuria, placental damage, and embryo resorption. Pre-administration of KPs significantly reduced hypertension, proteinuria, improved generalized endothelial dysfunction, and decreased levels of anti-HIF-1α, sFLT1, anti-TNF-α, and IL-6 in the placenta of SHRSP rats. In ex vivo CAM study, L-NAME administration in chicken embryos resulted in lower vessel density and hemorrhage; however, angiogenesis was observed after KPs-HD treatment. The results indicate that kefir peptides improve renal lesions, prevent renal parenchyma damage, and balance endothelial and angiogenic dysfunction in both maternal and fetal sites in L-NAME-induced SHRSP pregnant rats. [Display omitted] • KPs regulate angiogenic factors (sFlt-1/PlGF) in maternal-fetal circulation. • L-NAME-induced preeclampsia-like conditions in SHRSP rats was established. • KPs modulate eNOS/NO effects on embryonic vasculogenesis via glycolysis. • KPs exhibit anti-inflammatory properties, inhibiting HIF-1α and TNF-α signaling. • KPs show potential as a protective nutraceutical against preeclampsia. [ABSTRACT FROM AUTHOR]

It was previously shown that SHPL-49, a glycoside derivative of salidroside formed through structural modification, exhibited neuroprotective effects in a rat cerebral ischemia model of permanent middle cerebral artery occlusion (pMCAO). Additionally, SHPL-49 enhanced the mRNA expression of vascular endothelial growth factor-a (Vegf-a) in macrophages. Microglia, functioning as resident macrophages within the brain, promptly respond to cerebral ischemia and engage in interactions with the cells of the Glial-Vascular Unit to orchestrate nerve injury responses. We postulated that the neuroprotective effects of SHPL-49 were mediated through microglia-dependent amelioration of endothelial dysfunction following cerebral ischemia. The present study demonstrates that SHPL-49 effectively mitigated microglia-dependent endothelial dysfunction in the pMCAO model by upregulating the expression of VEGF and suppressing the release of MMP-9 from microglia. Further MRI analyses confirmed that SHPL-49 significantly reduced nerve and endothelial function when microglia were depleted in the brains of pMCAO rats. The above phenomenon was also confirmed in the in vitro experiment investigating microglia-mediated brain endothelial cell function. Furthermore, we discovered that SHPL-49 activates the VEGFR2/Akt/eNOS pathways in endothelial cells and suppresses the p38 MAPK/MMP-9 pathways in microglia cells, thereby facilitating brain endothelial cell protection. Altogether, we have demonstrated that SHPL-49 effectively ameliorates endothelial dysfunction induced by cerebral ischemia through a microglia-dependent mechanism, thereby providing more valuable insights and references for the clinical evaluation of SHPL-49 injection for ischemic stroke. • SHPL-49 can promote the M2 phenotype transformation of microglia and realize the precise regulation of VEGF. • This study reveals for the first time that SHPL-49 regulates microglia-mediated vascular endothelial function after cerebral ischemia. • The microglia-mediated protective effects of SHPL-49 were confirmed by microglial depletion in vivo. [ABSTRACT FROM AUTHOR]

Secreted proteins have gained more and more attentions, since they can become therapeutic targets, drugs and biomarkers for prevention, diagnosis and treatment of disease and aging. In 2014, Metrnl (also named Meteorin-like, Cometin, Subfatin, Interleukin-39, Interleukin-41, Meteorin-β, and Metrn-β/Metrnβ), as a novel secreted protein released from a certain tissue, was reported by us and others. During the past decade, the number of articles on Metrnl has continued to increase. Different sources of Metrnl have been described with different functions, including Metrnl as an adipokine for insulin sensitization, a cardiokine against cardiac hypertrophy and dysfunction, an endothelium-derived factor against endothelial dysfunction and atherosclerosis, etc. Especially, we show that endothelial Metrnl is a major source for circulating Metrnl levels. Meanwhile, lots of clinical studies have investigated the relationship between blood Metrnl levels and metabolic, inflammatory and cardiovascular diseases. Metrnl appears a protective factor and a promising therapeutic target and/or drug against these diseases, given the relatively consistent conclusion from the preclinical studies. In addition to graphically demonstrating the role of Metrnl in various organs and diseases, this review will mainly describe the discovery of Metrnl, summarize the role of Metrnl in cardiovascular system that is a recently major progress in Metrnl research, and highlight several perspectives for future basic and translational research. Also, we suggest using one name Metrnl instead of other multiple names for the same protein. [ABSTRACT FROM AUTHOR]

• Doxorubicin activates versatile pathways, mainly oxidative and calcium stress, endothelial and metabolic dysfunctions, topoisomerase, and glucose metabolism disturbances with a united endpoint—cardiomyopathy and associated heart failure. Over the years, advancements in the field of oncology have made remarkable strides in enhancing the efficacy of medical care for patients with cancer. These modernizations have resulted in prolonged survival and improved the quality of life for these patients. However, this progress has also been accompanied by escalation in mortality rates associated with anthracycline chemotherapy. Anthracyclines, which are known for their potent antitumor properties, are notorious for their substantial cardiotoxic potential. Remarkably, even after 6 decades of research, a conclusive solution to protect the cardiovascular system against doxorubicin-induced damage has not yet been established. A comprehensive understanding of the pathophysiological processes driving cardiotoxicity combined with targeted research is crucial for developing innovative cardioprotective strategies. This review seeks to explain the mechanisms responsible for structural and functional alterations in doxorubicin-induced cardiomyopathy. RAAS, renin-angiotensin-aldosterone system; HF, heart failure [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Cobalt chloride (CoCl2) induces hypoxia that cause irreversible cellular damage and endothelial dysfunction, making apoptosis inevitable. • Diosmin and bisoprolol, either alone or in combination, enhance heart function by reducing abnormalities in the electrocardiogram and the hypotension brought on by CoCl2. • Diosmin has been demonstrated to trigger autophagy in cardiac cells, therefore preventing hypoxia-induced cell death. • Our findings provided a significant correlation between their cardio-protective action and their ability to regulates hypoxia-related signaling, including IL-6/α-SMA, MiR-143-3p/MAPK/MCP-1, MiR-143-3p/ERK5/MCP-1, ERK5/CXCR4, and Orai-1/STIM-1/Ca2+ overload. • These inhibitory signaling interpret the antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic activity of bisoprolol and diosmin against CoCl2-induced cardiac injury. Even while accelerated cardiomyocyte apoptosis is one of the primary causes of cardiac damage, the underlying mechanism is still mostly unknown. In addition to examining potential protective effects of bisoprolol and diosmin against CoCl2-induced cardiac injury, the goal of this study was to identify potential mechanisms regulating the hypoxic cardiac damage caused by cobalt chloride (CoCl2). For a period of 21 days except Cocl2 14 days from the first day of the experiment, rats were split into the following groups: Normal control group, rats received vehicle only (2 ml/kg/day, p.o.), (Cocl2, 150 mg/kg/day, p.o.), bisoprolol (25 mg/kg/day, p.o.); diosmin (100 mg/kg/day, p.o.) and bisoprolol + diosmin + Cocl2 groups. At the end of the experimental period, serum was taken for estimation of cardiac function, lipid profile, and pro/anti-inflammatory cytokines. Moreover, tissue samples were collected for evaluation of oxidative stress, endothelial dysfunction, α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Diosmin and bisoprolol, either alone or in combination, enhance heart function by reducing abnormalities in the electrocardiogram and the hypotension brought on by CoCl2. Additionally, they significantly ameliorate endothelial dysfunction by downregulating the cardiac expressions of α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Bisoprolol and diosmin produced modulatory activity against inflammatory state, redox balance, and atherogenic index concurrently. Together, diosmin and bisoprolol, either alone or in combination, significantly reduced all the cardiac alterations brought on by CoCl2. The capacity to obstruct hypoxia-induced α-SMA, PKC-α, MiR-143-3P/MAPK/MCP-1, MiR-143-3P/ERK5/CXCR4, Orai-1/STIM-1 signaling activation, as well as their anti-inflammatory, antioxidant, and anti-apoptotic properties, may be responsible for these cardio-protective results. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a complex and multigenic pathology associated with significant epigenetic reprogramming. Traditional factors (age, sex, obesity, hyperglycaemia, dyslipidaemia, hypertension) and non-traditional factors (foetal indices, microbiome alteration, clonal hematopoiesis, air pollution, sleep disorders) induce endothelial dysfunction, resulting in reduced vascular tone and increased vascular permeability, inflammation and shear stress. These factors induce paracrine and autocrine interactions between several cell types, including vascular smooth muscle cells, endothelial cells, monocytes/macrophages, dendritic cells and T cells. Such cellular interactions lead to tissue-specific epigenetic reprogramming regulated by DNA methylation, histone modifications and microRNAs, which manifests in atherosclerosis. Our review outlines epigenetic signatures during atherosclerosis, which are viewed as potential clinical biomarkers that may be adopted as new therapeutic targets. Additionally, we emphasize epigenetic modifiers referred to as 'epidrugs' as potential therapeutic molecules to correct gene expression patterns and restore vascular homeostasis during atherosclerosis. Further, we suggest nanomedicine-based strategies involving the use of epidrugs, which may selectively target cells in the atherosclerotic microenvironment and reduce off-target effects. [ABSTRACT FROM AUTHOR]

Patients with systemic lupus erythematosus (SLE) experience greater cardiovascular morbidity and mortality compared to the general population. It is known that endothelial dysfunction, an early indicator of atherosclerosis development, can arise even without the presence of conventional cardiovascular risk factors. In fact, the risk factors contributing to cardiovascular disease can be classified into traditional risk factors and those uniquely associated with SLE such as disease activity, autoantibodies, etc.Furthermore, the pathogenesis of cardiovascular disease in SLE is linked to the activation of both the innate and adaptive immune systems. Given these findings, it is essential for clinicians to acknowledge the heightened CVD risk in SLE patients, perform comprehensive screenings for cardiovascular risk factors, and implement aggressive treatment strategies for those who exhibit signs of clinical CVD. The aim of this review is to summarize the findings on cardiovascular disease in SLE and to examine potential screening and therapeutic strategies for clinical practice. • Cardiovascular disease mortality is higher in systemic lupus erythematosus. • The pathogenesis of cardiovascular disease is related to the activation of both innate and adaptive immune system. • Cardiovascular disease risk factors included traditional and SLE-specific risk factors • Conventional, biological and target synthetic DMARDs can have a beneficial and/or adverse effects on atherosclerosis and cardiovascular disease • It is crucial for clinicians to recognize the increased comorbidity in SLE patients in order to initiate an aggressive treatment. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the efficacy of CRISPR/Cas9-mediated A4GALT suppression in rescuing endothelial dysfunction in Fabry disease (FD) endothelial cells (FD-ECs) derived from human induced pluripotent stem cells (hiPSCs). We differentiated hiPSCs (WT (wild-type), WTC-11), GLA -mutant hiPSCs (GLA- KO, CMC-Fb-002), and CRISPR/Cas9-mediated A4GALT -KO hiPSCs (GLA/A4GALT- KO, Fb-002- A4GALT -KO) into ECs and compared FD phenotypes and endothelial dysfunction. We also analyzed the effect of A4GALT suppression on reactive oxygen species (ROS) formation and transcriptome profiles through RNA sequencing. GLA -mutant hiPSC-ECs (GLA -KO and CMC-Fb-002) showed downregulated expression of EC markers and significantly reduced α-GalA expression with increased Gb-3 deposition and intra-lysosomal inclusion bodies. However, CRISPR/Cas9-mediated A4GALT suppression in GLA/A4GALT -KO and Fb-002- A4GALT -KO hiPSC-ECs increased expression levels of EC markers and rescued these FD phenotypes. GLA -mutant hiPSC-ECs failed to form tube-like structure in tube formation assays, showing significantly decreased migration of cells into the scratched wound area. In contrast, A4GALT suppression improved tube formation and cell migration capacity. Western blot analysis revealed that MAPK and AKT phosphorylation levels were downregulated while SOD and catalase were upregulated in GLA -KO hiPSC-ECs. However, suppression of A4GALT restored these protein alterations. RNA sequencing analysis demonstrated significant transcriptome changes in GLA -mutant EC, especially in angiogenesis, cell death, and cellular response to oxidative stress. However, these were effectively restored in GLA/A4GALT- KO hiPSC-ECs. CRISPR/Cas9-mediated A4GALT suppression rescued FD phenotype and endothelial dysfunction in GLA -mutant hiPSC-ECs, presenting a potential therapeutic approach for FD-vasculopathy. [Display omitted] • GLA -mutant hiPSC-ECs showed abnormal protein and RNA expression along with increased deposition of Gb3. • Gb3 deposition can induce endothelial dysfunction in GLA -mutant hiPSC-ECs. • Inhibition of A4GALT ameliorates endothelial dysfunction by reducing deposition of Gb3. [ABSTRACT FROM AUTHOR]