Search

BACKGROUND: Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt heart failure (HF). The prevalence of DbCM in patients with type 2 diabetes (T2D) is not well established. This study aims to determine prevalence of DbCM in adult T2D patients in real-world clinical practice. METHODS: Retrospective multi-step review of electronic medical records of patients with the diagnosis of T2D who had echocardiogram at UC San Diego Medical Center (UCSD) within 2010-2019 was conducted to identify T2D patients with SBHF. We defined pure DbCM when SBHF is associated solely with T2D and mixed SBHF when other medical conditions can contribute to SBHF. Pure DbCM was diagnosed in T2D patients with echocardiographic demonstration of SBHF defined as left atrial (LA) enlargement (LAE), as evidenced by LA volume index ≥ 34 mL/m2, in the presence of left ventricular ejection fraction (LVEF) ≥ 45%, while excluding overt HF and comorbidities that can contribute to SBHF. RESULTS: Of 778,314 UCSD patients in 2010-2019, 45,600 (5.9%) had T2D diagnosis. In this group, 15,182 T2D patients (33.3%) had echocardiogram and, among them, 13,680 (90.1%) had LVEF ≥ 45%. Out of 13,680 patients, 4,790 patients had LAE. Of them, 1,070 patients were excluded due to incomplete data and/or a lack of confirmed T2D according to the American Diabetes Association recommendations. Thus, 3,720 T2D patients with LVEF ≥ 45% and LAE were identified, regardless of HF symptoms. In this group, 1,604 patients (43.1%) had overt HF and were excluded. Thus, 2,116 T2D patients (56.9% of T2D patients with LVEF ≥ 45% and LAE) with asymptomatic SBHF were identified. Out of them, 1,773 patients (83.8%) were diagnosed with mixed SBHF due to comorbidities such as hypertension (58%), coronary artery disease (36%), and valvular heart disease (17%). Finally, 343 patients met the diagnostic criteria of pure DbCM, which represents 16.2% of T2D patients with SBHF, i.e., at least 2.9% of the entire T2D population in this study. CONCLUSIONS: Our findings provide insights into prevalence of DbCM in real-world clinical practice and indicate that DbCM affects a significant portion of T2D patients.

Background and Purpose Experimental Approach Key Results Conclusion and Implications Sarcoplasmic reticulum Ca2+‐ATPase (SERCA2a) is impaired in heart failure. Phosphodiesterases (PDEs) are implicated in the modulation of local cAMP signals and protein kinase A (PKA) activity essential for cardiac function. We characterise PDE isoforms that underlie decreased activities of SERCA2a and reduced cardiac contractile function in diabetic cardiomyopathy.Wild type mice were fed with either normal chow or a high‐fat diet (HFD). Cardiomyocytes were isolated for excitation–contraction coupling (ECC), fluorescence resonant energy transfer PKA biosensor and proximity ligation assays.The upregulated PDE4D3 and PDE4D9 isoforms in HFD cardiomyocytes specifically bound to SERCA2a but not ryanodine receptor 2 (RyR2) on the sarcoplasmic reticulum (SR). The increased association of PDE4D isoforms with SERCA2a in HFD cardiomyocytes led to reduced local PKA activities and phosphorylation of phospholamban (PLB) but minimally effected the PKA activities and phosphorylation of RyR2. These changes correlate with slower calcium decay tau in the SR and attenuation of ECC in HFD cardiomyocytes. Selective inhibition of PDE4D3 or PDE4D9 restored PKA activities and phosphorylation of PLB at the SERCA2a complex, recovered calcium decay tau, and increased ECC in HFD cardiomyocytes. Therapies with PDE4 inhibitor roflumilast, PDE4D inhibitor BPN14770 or genetical deletion of PDE4D restored PKA phosphorylation of PLB and cardiac contractile function.The current study identifies upregulation of specific PDE4D isoforms that selectively inhibit SERCA2a function in HFD‐induced cardiomyopathy, indicating that this remodelling can be targeted to restore cardiac contractility in diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DC) leads to heart failure, with few effective approaches for its intervention. Eicosapentaenoic acid (EPA) is an essential nutrient that benefits the cardiovascular system, but its effect on DC remains unknown. Here, we report that EPA protects against DC in streptozotocin and high-fat diet-induced diabetic mice, with an emphasis on the reduction of cardiac M1-polarized macrophages. In vitro, EPA abrogates cardiomyocyte injury induced by M1-polarized macrophages, switching macrophage phenotype from M1 to Mox, but not M2, polarization. Moreover, macrophage Mox polarization combats M1-polarized macrophage-induced cardiomyocyte injury. Further, heme oxygenase 1 (HO-1) was identified to maintain the Mox phenotype, mediating EPA suppression of macrophage M1 polarization and the consequential cardiomyocyte injury. Mechanistic studies reveal that G-protein-coupled receptor 120 mediates the upregulation of HO-1 by EPA. Notably, EPA promotes Mox polarization in monocyte-derived macrophages from diabetic patients. The current study provides EPA and macrophage Mox polarization as novel strategies for DC intervention. Synopsis: Eicosapentaenoic acid (EPA) prevents diabetic cardiomyopathy (DC) by promoting the transition of macrophages from M1 to Mox polarization. Heme oxygenase 1 (HO-1) mediates EPA suppression of macrophage M1 polarization and M1-induced cardiomyocyte injury. EPA prevented DC by switching macrophage polarization from M1 to Mox phenotype. HO-1 acts as a keystone in maintaining macrophage Mox phenotype, mediating EPA's protection. EPA promotes Mox polarization in human macrophages from patients with type 2 diabetes. EPA activates HO-1 expression via GPR120 in M1 polarized macrophages. Eicosapentaenoic acid (EPA) prevents diabetic cardiomyopathy (DC) by promoting the transition of macrophages from M1 to Mox polarization. Heme oxygenase 1 (HO-1) mediates EPA suppression of macrophage M1 polarization and M1-induced cardiomyocyte injury. [ABSTRACT FROM AUTHOR]

Background: Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway. Methods: To elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) administration, and AC16 human cardiomyocyte cell subjected to stimulation with high glucose (HG) and palmitic acid (PA). These models were employed to assess the changes in the senescence phenotype of cardiomyocytes and cardiac function following treatment with SGLT2i. Concurrently, we identified ANGPTL4, a key factor contributing to senescence in DCM, using RNA sequencing (RNA-seq) technology and bioinformatics methods. We further clarified ANGPTL4 role in promoting pathological aging of cardiomyocytes induced by hyperglycemia and hyperlipidemia through knockdown and overexpression of the factor, as well as analyzed the impact of SGLT2i intervention on ANGPTL4 expression. Additionally, we utilized chromatin immunoprecipitation followed by quantitative real-time PCR (ChIP-qPCR) to confirm that FOXO1 is essential for the transcriptional activation of ANGPTL4. Results: The therapeutic intervention with SGLT2i alleviated the senescence phenotype in cardiomyocytes of the DCM mouse model constructed by high-fat feeding combined with STZ, as well as in the AC16 model stimulated by HG and PA, while also improving cardiac function in DCM mice. We observed that the knockdown of ANGPTL4, a key senescence-promoting factor in DCM identified through RNA-seq technology and bioinformatics, mitigated the senescence of cardiomyocytes, whereas overexpression of ANGPTL4 exacerbated it. Moreover, SGLT2i improved the senescence phenotype by suppressing the overexpression of ANGPTL4. In fact, we discovered that SGLT2i exert their effects by regulating the upstream transcription factor FOXO1 of ANGPTL4. Under conditions of hyperglycemia and hyperlipidemia, compared to the control group without FOXO1, the overexpression of FOXO1 in conjunction with SGLT2i intervention significantly reduced both ANGPTL4 mRNA and protein levels. This suggests that the FOXO1-ANGPTL4 axis may be a potential target for the cardioprotective effects of SGLT2i. Conclusions: Collectively, our study demonstrates that SGLT2i ameliorate the pathological aging of cardiomyocytes induced by a high glucose and high fat metabolic milieu by regulating the interaction between FOXO1 and ANGPTL4, thereby suppressing the transcriptional synthesis of the latter, and consequently restoring cardiac function. [ABSTRACT FROM AUTHOR]

Objectives: The pathophysiology of diabetic cardiomyopathy (DCM) is a phenomenon of great interest, but its clinical problems have not yet been effectively addressed. Recently, the mechanism of ferroptosis in the pathophysiology of various diseases, including DCM, has attracted widespread attention. Here, we explored the role of PACS2 in ferroptosis in DCM through its downregulation of PACS2 expression. Methods and results: Cardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues. Conclusions: The PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function. [ABSTRACT FROM AUTHOR]

As a consequence of chronic hyperglycemia, diabetes complications and tissue damage are exacerbated. There is evidence that natural phytochemicals, including resveratrol, a bioactive polyphenol, may be able to reduce oxidative stress and improve insulin sensitivity. However, resveratrol's limited bioavailability hampers its therapeutic effectiveness. By using liposomes, resveratrol may be better delivered into the body and be more bioavailable. The objective of this study was to assess the cardioprotective potential of liposome-encapsulated resveratrol (LR) in a streptozotocin-induced (STZ) diabetic rat model. Adult male Wistar rats were categorized into five groups: control, diabetic, resveratrol-treated (40 mg/kg), liposomal resveratrol (LR)-treated (20 mg/kg) and liposomal resveratrol (LR)-treated (40 mg/kg) for a five-week study period. We compared the effects of LR to those of resveratrol (40 mg/kg) on various parameters, including serum levels of cardiac markers, tissue levels of pro-inflammatory cytokines, nuclear transcription factor, oxidative stress markers, and apoptotic markers. LR treatment in STZ-diabetic rats resulted in notable physiological improvements, including blood glucose regulation, inflammation reduction, oxidative stress mitigation, and apoptosis inhibition. LR effectively lowered oxidative stress and enhanced cardiovascular function. It also demonstrated a remarkable ability to suppress NF-kB-mediated inflammation by inhibiting the pro-inflammatory cytokines TNF-α and IL-6. Additionally, LR restored the antioxidant enzymes, catalase and glutathione peroxidase, thereby effectively counteracting oxidative stress. Notably, LR modulated apoptotic regulators, including caspase, Bcl2, and Bax, suggesting a role in regulating programmed cell death. These biochemical alterations were consistent with improved structural integrity of cardiac tissue as revealed by histological examination. In comparison, resveratrol exhibited lower efficacy at an equivalent dosage. Liposomal resveratrol shows promise in alleviating hyperglycemia-induced cardiac damage in diabetes. Further research is warranted to explore its potential as a therapeutic agent for diabetic cardiovascular complications and possible cardioprotective effects. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy is a condition characterized by ventricular dysfunction in diabetic patients that is not caused by other cardiac ailments. It is associated with factors such as left ventricular hypertrophy, metabolic disturbances, and oxidative stress. Tight junctions, which form a barrier between cells, play a role in the vascular complications of diabetes. Proteins such as claudins and occludens are important for the structure and function of tight junctions. Zona occludens (ZO) proteins are also involved in tight junctions and their expression may be affected by diabetes. The review discusses the impact of diabetes on the tight junctions and the role of ZO proteins in diabetic cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the major causes of ischemic and nonischemic heart failure. While hypertension and coronary artery disease are frequent comorbidities in patients with diabetes, cardiac contractile dysfunction and remodeling occur in diabetic patients even without comorbidities, which is referred to as diabetic cardiomyopathy. Investigations in recent decades have demonstrated that the production of reactive oxygen species (ROS), impaired handling of intracellular Ca2+, and alterations in energy metabolism are involved in the development of diabetic cardiomyopathy. AMP deaminase (AMPD) directly regulates adenine nucleotide metabolism and energy transfer by adenylate kinase and indirectly modulates xanthine oxidoreductase-mediated pathways and AMP-activated protein kinase-mediated signaling. Upregulation of AMPD in diabetic hearts was first reported more than 30 years ago, and subsequent studies showed similar upregulation in the liver and skeletal muscle. Evidence for the roles of AMPD in diabetes-induced fatty liver, sarcopenia, and heart failure has been accumulating. A series of our recent studies showed that AMPD localizes in the mitochondria-associated endoplasmic reticulum membrane as well as the sarcoplasmic reticulum and cytosol and participates in the regulation of mitochondrial Ca2+ and suggested that upregulated AMPD contributes to contractile dysfunction in diabetic cardiomyopathy via increased generation of ROS, adenine nucleotide depletion, and impaired mitochondrial respiration. The detrimental effects of AMPD were manifested at times of increased cardiac workload by pressure loading. In this review, we briefly summarize the expression and functions of AMPD in the heart and discuss the roles of AMPD in diabetic cardiomyopathy, mainly focusing on contractile dysfunction caused by this disorder. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a major complication of diabetes. Transient receptor potential melastatin 2 (TRPM2) activity increases in diabetic oxidative stress state, and it is involved in myocardial damage and repair. We explore the protective effect of TRPM2 knockdown on the progression of DCM. A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100-mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in heart was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 9 carrying TRPM2 shRNA. Neonatal rat ventricular myocytes was exposed to 45 mM of high-glucose (HG) stimulation for 72 h in vitro to mimic the in vivo conditions. Western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry and fluorescence, electron, CCK-8, and flow cytometry were used to evaluate the phenotype of cardiac inflammation, fibrosis, apoptosis, and autophagy. Mice with HFD/STZ-induced diabetes exhibited systolic and diastolic dysfunction, as demonstrated by increased myocardial apoptosis and autophagy inhibition in the heart. Compared to control group, the protein expression of TRPM2, bax, cleaved caspase-3, and P62 was significantly elevated, and the protein expression of bcl-2 and LC3-II was significantly decreased in the myocardial tissues of the HFD/STZ-induced diabetes group. Knockdown of TRPM2 significantly reversed the HFD/STZ-induced myocardial apoptosis and autophagy inhibition. TRPM2 silencing attenuated HG-induced apoptosis and autophagy inhibition in primary cardiomyocytes via regulating the MEK/ERK mTORC1 signaling pathway. TRPM2 knockdown attenuates hyperglycemia-induced myocardial apoptosis and promotes autophagy in HFD/STZ-induced diabetic mice or HG-stimulated cardiomyocytes via regulating the MEK/ERK and mTORC1 signaling pathway. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DbCM) is one of the most common vascular complications of diabetes, and can cause heart failure and threaten the life of patients. The pathogenesis is complex, and key genes have not fully identified. In this study, bioinformatics analysis was used to predict DbCM-related gene targets. Published datasets from the NCBI Gene Expression Omnibus with accession numbers GSE62203 and GSE197850 were selected for analysis. Differentially expressed genes (DEGs) were identified by the online tool GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID online database. Protein–protein interaction network construction and hub gene identification were performed using STRING and Cytoscape. We used 30 mM and 1 μM hydrocortisone-stimulated AC16 cells as an in vitro model of diabetic cardiomyopathy. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression levels of hub genes. A total of 73 common DEGs were identified in both datasets, including 47 upregulated and 26 downregulated genes. GO and KEGG pathway enrichment analyses revealed that the DEGs were significantly enriched in metabolism, hypoxia response, apoptosis, cell proliferation regulation, and cytoplasmic and HIF signalling pathways. The top 10 hub genes were LDHA, PGK1, SLC2A1, ENO1, PFKFB3, EGLN1, MYC, PDK1, EGLN3 and BNIP3. In our in vitro study, we found that PGK1, SLC2A1, PFKFB3, EGLN1, MYC, EGLN3 and BNIP3 were upregulated, ENO1 was downregulated, and LDHA was unchanged. Except for PGK1 and ENO1, these hub genes have been previously reported to be involved in DbCM. In summary, we identified DEGs and hub genes and first reported PGK1 and ENO1 in DbCM, which may serve as potential candidate genes for DbCM targeted therapy. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a severe cardiovascular complication of diabetes characterized by myocardial hypertrophy, fibrosis, and impaired cardiac function. Fibroblast growth factor 21 (FGF21) has emerged as a promising therapeutic target due to its antifibrotic, antioxidant, and anti-inflammatory properties. Our commentary summarizes and affirms the recent study by Wang et al., which demonstrates the significant role of ferroptosis in DCM pathogenesis. FGF21 has shown promise as a therapeutic target for DCM, potentially inhibiting ferroptosis, mitigating oxidative damage, and protecting cardiomyocyte function. Mechanistically, the study identified ATF4 as an upstream regulator of FGF21 in DCM, revealing that FGF21 directly interacts with ferritin and extends its half-life, thus inhibiting ferroptosis in DCM. These findings provide a theoretical basis for understanding the pathogenesis and treatment of DCM. Our commentary suggests that future studies should explore the role of non-cardiomyocyte cell types in DCM, verify findings with clinical samples, and address comprehensive methods for ferroptosis detection. Additionally, we discuss the clinical application and future potential of FGF21-based therapies for DCM. Such efforts may contribute to advancing DCM diagnosis and treatment, fostering the development of innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is defined as structural and functional cardiac abnormalities in diabetes, and cardiomyocyte death is the terminal event of DCM. Ferroptosis is iron-dependent oxidative cell death. Evidence has indicated that iron overload and ferroptosis play important roles in the pathogenesis of DCM. Mitochondria, an important organelle in iron homeostasis and ROS production, play a crucial role in cardiomyocyte ferroptosis in diabetes. Studies have shown some anti-diabetic medicines, plant extracts, and ferroptosis inhibitors might improve DCM by alleviating ferroptosis. In this review, we systematically reviewed the evidence of ferroptosis in DCM. Anti-ferroptosis might be a promising therapeutic strategy for the treatment of DCM. [ABSTRACT FROM AUTHOR]

Background: This study investigates the impact of a high‐sugar environment on H9C2 cardiomyocytes and explores the protective effects of carvedilol in the context of diabetic cardiomyopathy (Dia‐CM). Transcriptomic analysis identified 21,655 differentially expressed genes associated with Dia‐CM, demonstrating significant separation among samples. Methods: H9C2 cardiomyocytes were cultured in a high‐sugar environment to simulate Dia‐CM conditions. Cell viability, cytokine levels, and protein expression were assessed using CCK‐8 assays, ELISA, and Western blot techniques. Intervention experiments with NLRP3, caspase‐1, and ROS inhibitors were conducted to evaluate their protective effects. The therapeutic potential of carvedilol was assessed by examining its impact on cell viability, cytokine levels, and key biomarkers. An in‐depth analysis of carvedilol's regulatory effects on ROS and key proteins in H9C2 cells was also conducted. Results: In vitro, a high‐sugar environment significantly reduced H9C2 cell survival, increased ROS levels, activated inflammatory responses, and upregulated NLRP3, caspase‐1, and GSDMD‐N proteins. Inhibitors of NLRP3, caspase‐1, and ROS ameliorated these effects. Carvedilol treatment improved cell activity, reduced inflammatory cytokine levels, suppressed ROS production, and downregulated NLRP3, pro‐caspase‐1, GSDMD‐N, and p‐NF‐κB proteins. Moderate‐dose carvedilol exhibited optimal intervention effects. Conclusions: A high‐sugar environment induces cardiomyocyte damage through ROS production and NLRP3 inflammasome activation. Inhibitors of NLRP3, caspase‐1, and ROS provide effective protection. Carvedilol significantly mitigates the detrimental effects of a high‐sugar environment on H9C2 cardiomyocytes, potentially through inhibiting the NLRP3‐ASC inflammasome and caspase‐1/GSDMD‐dependent signaling pathway‐mediated pyroptosis. These findings offer insights into Dia‐CM mechanisms and highlight carvedilol as a promising therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Diabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated. Methods: In vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS. Results: GAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling. Conclusion: GAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a severe cardiac complication of diabetes mellitus, characterized by structural and functional myocardial abnormalities. The molecular mechanisms underlying DCM, particularly the role of dual-specificity phosphatase 26 (DUSP26), remain insufficiently understood. Our study reveals that DUSP26 expression is markedly downregulated in the cardiomyocytes of diabetic db / db mice and under glucolipotoxic stress. Overexpression of DUSP26 in db / db mice significantly improved cardiac function, as demonstrated by enhanced left ventricular ejection fraction and fractional shortening, alongside reduced myocardial fibrosis and hypertrophy. Mitochondrial analysis indicated that DUSP26 overexpression led to increased ATP production, enhanced mitochondrial fusion, and improved structural integrity. In addition, lipid accumulation was reduced, reflecting enhanced metabolic function. We also discovered that DUSP26 is necessary for regulating the focal adhesion kinase (FAK)-extracellular signal-regulated kinase (ERK) pathway, with pharmacological activation of FAK partially offsetting the benefits of DUSP26 overexpression in rescue experiments. These findings underscore the pivotal role of DUSP26 as a potential therapeutic target, highlighting the importance of developing targeted molecular interventions to address diabetic cardiac complications. The role of DUSP26 in cardiomyocytes response to metabolic stress in DCM. [Display omitted] • Glucolipotoxic stress downregulates DUSP26 expression in cardiomyocytes. • DUSP26 overexpression improves cardiac function in diabetic cardiomyopathy. • DUSP26 regulates mitochondrial dynamics and lipid metabolism under glucolipotoxicity. • DUSP26 influences mitochondrial function through the FAK-ERK signaling axis. [ABSTRACT FROM AUTHOR]

Background: Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A4 (LXA4), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA4 therapeutic treatment attenuates diabetes-induced cardiac pathology. Methods: Six-week-old male apolipoprotein E-deficient (ApoE−/−) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot. Results: As expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA1c) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control. Conclusions: These findings demonstrated that LXA4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA4-based therapy for the management of diabetic heart disease. The recent development of stable LXA4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic cardiomyopathy (DCM) is a significant complication of diabetes, characterized primarily by the development of heart failure in individuals with diabetes. Numerous animal studies have indicated that resveratrol enhances cardiac function in diabetic cardiomyopathy; however, its reliability and underlying mechanism remain unclear. This study aims to assess the cardioprotective effects of resveratrol on DCM and explore its potential mechanism. Methods: We searched PubMed, EMBASE, WOS, Cochrane Library, CNKI, CBM, Chinese VIP, and Wan Fang Database until March 31st, 2024, without language restrictions. Continuous outcome measures were analyzed using weighted mean difference or standardized mean difference, and heterogeneity was assessed with I2. The risk of bias in animal experiments was evaluated using the SYRCLE tool, and evidence reliability was determined with the GRADE tool. All data were analyzed using Review Manager 5.4.1 and Stata 17. This study has been registered on the PROSPERO (CRD42024523944). Results: A total of 18 studies meeting the criteria were identified. The analysis revealed that the resveratrol intervention group exhibited significant improvements in LVEF (WMD = 17.88), LVFS (WMD = 8.77), HW/BW (SMD=-2.92), SOD (SMD = 4.53), and MDA (SMD=-5.07) compared to the control group. The GRADE grading assessment indicated moderate certainty for LVEF, HW/BW, and MDA, while certainty for other factors was considered low. Conclusion: Our research suggests that resveratrol may protect cardiac function in DCM through anti-inflammatory and anti-oxidative stress effects. However, these findings are based on preclinical data, and further extensive trials are needed to confirm their effectiveness and safety before clinical application. [ABSTRACT FROM AUTHOR]

Objective: To measure the plasma levels of human cartilage intermediate layer protein 1 (CILP1) in patients with diabetic cardiomyopathy (DCM), and to investigate its association with the occurrence of major adverse cardiovascular events (MACE) in DCM. Methods: A total of 336 diabetic patients were enrolled and assigned into two groups based on the presence or absence of DCM (DCM group and N-DCM group). The baseline clinical data including glutamic-pyruvic transaminase (ALT), glutamic oxaloacetic acid transferase (AST), albumin, serum creatinine, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), and N-terminal pro brain natriuretic peptide (NT-proBNP) were recorded. Subsequently, plasma levels of CILP1 at admission were detected by the enzyme linked immunosorbent assay (ELISA) method. Echocardiographic parameters were also acquired for all patients. The association of CILP1 with LVEF, LVDD and CRP was determined. In addition, the occurrence of MACE was examined during the 12-month follow-up in the DCM group. Results: The concentration of CILP1 in the DCM group was higher than in the N-DCM group [1329.97 (1157.14, 1494.36) ng/L vs. 789.00 (665.75, 937.06) ng/L, P < 0.05], higher in the MACE group than in the non-MACE group [1777.23 (1532.83, 2341.26)ng/L vs. 885.00 (722.40, 1224.91) ng/L, P < 0.05). Correlation analysis revealed that CILP1 expression was associated with LVEF, CRP and LVDD (r = -0.58, 0.29 and 0.44, respectively, P < 0.05). Analysis of a nomogram demonstrated that CILP1, sex, age, BMI, LVEF and LVDD could predict the occurrence of MACE in DCM patients at 12 months (P < 0.05). The plasma levels of CILP1 were independently associated with a stronger discriminating power for DCM. Furthermore, inclusion of CILP1 as a covariate in the model caused a significant improvement in risk estimation compared with traditional risk factors for DCM [BASIC: AUC: 0.556, 95%CI: 0.501–0.610; BASIC + CILP1: AUC: 0.913, 95%CI: 0.877–0.941, P < 0.05] and MACE [BASIC: AUC: 0.710, 95%CI: 0.616–0.792; BASIC + CILP1: AUC: 0.871, 95%CI: 0.794–0.928, P < 0.05]. Conclusions: The serum concentration of CILP1 was increased in DCM patients. Elevated fasting plasma CILP1 levels was a robust diagnostic marker of DCM and was independently associated with an increased risk of MACE. [ABSTRACT FROM AUTHOR]

Introduction: As one of the most common complications of diabetes, diabetic cardiomyopathy (DCM) is the main cause of heart failure in patients with diabetes. However, the lack of effective treatments for DCM remains a clinical challenge. (Pro) renin receptor (PRR) is a member of renin angiotensin aldosterone system (RAAS). Here, we aim to determine whether PRR is involved in myocardial pyroptosis in diabetic cardiomyopathy. Methods: We established diabetic rats model by intraperitoneal injection of streptozotocin (STZ). PRR overexpression adenovirus or PRR knockdown adenovirus was injected into the tail vein. Western blot, histopathology and immunohistochemistry staining, ELISA and Echocardiography were used to detect cardiac function changes and myocardial injury levels of DCM rats. Primary cardiomyocytes were stimulated with high glucose and PRR overexpression or PRR knockdown was achieved by adenovirus transfection, we also used the inhibitor of AMPK to decrease the activity of AMPK. Western blot, Real-time PCR, Immunofluorescence and ELISA were used to detect the level of PRR and pyroptosis in cardiomyocyte. Results: We found that high glucose increased the expression of PRR in heart. After overexpression of PRR, the expression of the pyroptosis related proteins such as Caspase-1, IL-1β, IL-18, and NLRP3 was significantly increased, the phosphorylation level of AMPK was significantly decreased, and the fibrosis level was significantly increased, thus aggravating the cardiac function injury of DCM. On the contrary, PRR knockdown can alleviate the level of myocardial pyroptosis in DCM and improve cardiac function. The related mechanism was that PRR could inhibit AMPK phosphorylation and promote the activation of NLRP3 inflammasome. Discussion: PRR aggravated pyroptosis of cardiomyocyte, increased the dysfunction of cardiomyocyte, and may be related to the decrease of AMPK phosphorylation and the overactivation of NLRP3. This may provide new ideas and targets for the treatment of DCM. [ABSTRACT FROM AUTHOR]

Background: Although the exact role of mitophagy in the pathogenesis of diabetic cardiomyopathy (DCM) caused by type 2 diabetes mellitus (T2DM) remains controversial, recent studies revealed inhibition of mitophagy exacerbates cardiac injury in DCM. The zinc transporter ZIP7 has been reported to be upregulated by high glucose in cardiomyocytes and ZIP7 upregulation leads to inhibition of mitophagy in mouse hearts in the setting of ischemia/reperfusion. Nevertheless, little is known about the role of ZIP7 and its relationship with mitophagy in DCM caused by T2DM. Methods: T2DM was induced with high-fat diet (HFD) and streptozotocin. The cardiac-specific ZIP7 conditional knockout (ZIP7 cKO) mice were generated by adopting CRISPR/Cas9 system. Cardiac function was evaluated with echocardiography. Mitophagy was assessed by detecting mito-LC3II, mitoKeima, and mitoQC. Reactive oxygen species (ROS) were detected with DHE and mitoB. Results: ZIP7 was upregulated by T2DM in mouse hearts and ZIP7 cKO reduced mitochondrial ROS generation in mouse hearts with T2DM. Mitophagy was suppressed by T2DM in mouse hearts, which was prevented by ZIP7 cKO. T2DM inhibited PINK1 and Parkin accumulation in cardiac mitochondria, an effect that was prevented by ZIP7 cKO, pointing to that ZIP7 upregulation mediates T2DM-induced suppression of mitophagy by inhibiting the PINK1/Parkin pathway. T2DM induced mitochondrial hyperpolarization and decrease of mitochondrial Zn2+ and this was blocked by ZIP7 cKO, indicating that upregulation of ZIP7 leads to mitochondrial hyperpolarization by reducing Zn2+ within mitochondria. Finally, ZIP7 cKO prevented cardiac dysfunction and fibrosis caused by T2DM. Conclusions: ZIP7 upregulation mediates the inhibition of mitophagy by T2DM in mouse hearts by suppressing the PINK1/Parkin pathway. Reduction of mitochondrial Zn2+ due to upregulation of ZIP7 accounts for the inhibition of the PINK1/Parkin pathway. Prevention of ZIP7 upregulation is essential for the treatment of T2DM-induced cardiomyopathy. [ABSTRACT FROM AUTHOR]

The correction notice in Scientific Reports addresses errors in figure assembly in the article "Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy." The errors specifically affect the Western blotting results of Akt, Lamin B1, and β-actin in Figures 5, 7, and 8. Despite these errors, the scientific conclusions of the article remain unchanged. The correction was reported by Bin Zhang, Qiang Shen, Yaping Chen, Ruile Pan, Shihuan Kuang, Guiyan Liu, Guibo Sun, and Xiaobo Sun. [Extracted from the article]

Introduction: Cardiac hypertrophy is a compensatory stress response produced by a variety of factors, and pathologic hypertrophy can lead to irreversible, severe cardiac disease. Glycosphingolipids (GSLs) are vital constituents of cells, and changes in their content and composition are important factors causing mitochondrial dysfunction in diabetic cardiomyopathy; however, the relationship between GSLs expression and cardiac hypertrophy and specific mechanisms associated with it are not clear. Methods: Here, using male C57BL/6 mice, we performed aortic arch reduction surgery to establish an animal model of pressure overload cardiac hypertrophy. In addition, phenylephrine was used in vitro to induce H9c2 cells and neonatal rat left ventricular myocytes (NRVMs) to establish a cellular hypertrophy model. Results: Mass spectrometry revealed that the composition of GSLs was altered in pressure overload-induced hypertrophied mouse hearts and in stimulated hypertrophied cardiomyocyte cell lines. Specifically, in both cases, the proportion of endogenous lactosylceramide (LacCer) was significantly higher than in controls. Inhibition of GSL synthesis with Genz-123346 in NRVMs reduced cell hypertrophy, as well as fibrosis and apoptosis. By Western blotting, we detected decreased intracellular expression of Sirt3 and elevated phosphorylation of JNK after phenylephrine stimulation, but this was reversed in cells pretreated with Genz-123346. Additionally, increased protein expression of FoxO3a and Parkin, along with a decreased LC3-II/I protein ratio in phenylephrine-stimulated cells (compared with unstimulated cells), indicated that the mitochondrial autophagy process was disrupted; again, pretreatment with Genz-123346 reversed that. Discussion: Our results revealed that changes in GSLs in cardiomyocytes, especially an increase of LacCer, may be a factor causing cellular hypertrophy, which can be alleviated by inhibition of GSLs synthesis. A possible mechanism is that GSLs inhibition increases the expression of Sirt3 protein, scavenges intracellular reactive oxygen species, and restores mitochondrial autophagy homeostasis, thereby lessening cardiomyocyte hypertrophy. In all, these results provide a new perspective for developing drugs for cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Aim The effect of miR-223-3p on H9c2 cells in high glucose environments was investigated through bioinformatics and its role in the mechanism of development of diabetic cardiomyopathy was analyzed in conjunction with transcriptomic sequencing results. The objective was to identify novel therapeutic targets at the molecular level and explore the specific mechanisms of action of miR-223-3p. Methods In high glucose-cultivated H9c2 cells, miR-223-3p inhibition and control were transfected, respectively. RT-qPCR was used to detect the differences in miR-222-3p expression between the two cell groups. Differential mRNA was identified through high-throughput sequencing. GO functional analysis was conducted using TopGO software. DESeq2 software (v1. 16. 1) filtered differentially expressed genes and analyzed them using a miR-223-3p target gene database. This process predicted the target genes of miR-223-3p and validated the changes in their expression through RT-qPCR. Results The activity of H9c2 cells treated with high glucose decreased significantly. Significant differences in gene expression between the control group and the inhibitor group had been indicated by transcriptomic sequencing results. GO function enrichment analysis showed that the predicted target gene set was significantly enriched in G protein-coupled receptor activity, glycerol ether monooxygenase activity, cellular anion homeostasis, and chloride ion homeostasis, among others. KEGG pathway enrichment analysis further showed that these genes were mainly involved in the TNF signaling pathway and the IL-17 signaling pathway. In addition, they were related to type 1 diabetes, cytochrome P450 metabolism of exogenous drugs, and other diseases and physiological processes. Target gene prediction suggested that miR-223-3p may be associated with the expression changes of Cxcl10, Creb3l3, Mmp3, and Bcl3, among others. Conclusion The prediction of miR-223-3p and its downstream target genes in high glucose induced H9c2 cell injury may provide new targets for the treatment of diabetic cardiomyopathy, which [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the most prevalent global public health issues associated with a higher risk of cardiovascular diseases, contributing to morbidity and mortality. Research has demonstrated that elevated reactive oxygen species (ROS) generation in diabetes can trigger apoptosis, exacerbating diabetic cardiomyopathy (DCM). This study investigates the cardioprotective effects of Paederia foetida in rats’ models of type 2 diabetes induced by a high-fat diet (HFD) and streptozotocin (STZ) treatment. The diabetic model was established in Sprague Dawley rats by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg). Sprague Dawley rats were treated with varied concentrations of standardized extract of P. foetida (50 mg/kg and 100 mg/kg), administered orally once daily for four weeks. Standardized extract from P. foetida has a range of therapeutic potential, including anti-inflammatory, antioxidant, and anti-diabetic properties. The common metabolic disorder indices and myocardial apoptosis were investigated. The findings from this study demonstrated increased expression of Bcl-2 and decreased expression of Bcl-2 Associated X-protein BAX as indicated by IRS scoring in cardiomyocytes, suggesting that P. foetida has a significant protective effect on diabetic cardiomyopathy by decreasing apoptosis. Increased Bcl-2 and decreased BAX levels may be related to regulating oxidative stress and mitochondrial pathways involving myocardial apoptosis. P. foetida extract could be a potential intervention for attenuating cardiomyopathy in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Cellular senescence is a state of permanent cell cycle arrest and plays an important role in many vascular lesions. This study found that the cells of diabetic patients have more characteristics of senescence, which may cause microvascular complications. Cell senescence, as one of the common fates of cells, links microangiopathy and diabetes. Cell senescence in a high-glucose environment can partially elucidate the mechanism of diabetic microangiopathy, and various types of cellular senescence induced by it can promote the progression of diabetic microangiopathy. Still, the molecular mechanism of microangiopathy-related cellular senescence has not yet been clearly studied. Building on recent research evidence, we herein summarize the fundamental mechanisms underlying the development of cellular senescence in various microangiopathies associated with diabetes. We gradually explain how cellular senescence serves as a key driver of diabetic microangiopathy. At the same time, the treatment of basic senescence mechanisms such as cellular senescence may have a great impact on the pathogenesis of the disease, may be more effective in preventing the development of diabetic microangiopathy, and may provide new ideas for the clinical treatment and prognosis of diabetic microangiopathy. [ABSTRACT FROM AUTHOR]

Background: Intensive glycemic control is insufficient to reduce the risk of heart failure in patients with diabetes mellitus. While the hyperglycemic memory in the diabetic cardiomyopathy has been well documented, its underlying mechanisms are not fully understood. The present study tried to investigate whether the dysregulated proteins/biological pathways, which persistently altered in diabetic hearts during normoglycemia, participate in the hyperglycemic memory. Methods: Hearts of streptozotocin‐induced diabetic mice, with or without intensive glycemic control using slow‐release insulin implants, were collected. Proteins from total heart samples and subcellular fractions were assessed by mass spectrometry, Western blotting, and KEGG pathway enrichment analysis. mRNA sequencing was used to determine whether the persistently altered proteins were regulated at the transcriptional or post‐transcriptional level. Results: Western blot validation of several proteins with high pathophysiological importance, including MYH7, HMGCS2, PDK4, and BDH1, indicated that mass spectrometry was able to qualitatively, but not quantitatively, reflect the fold changes of certain proteins in diabetes. Pathway analysis revealed that the peroxisome, PPAR pathway, and fatty acid metabolism could be efficiently rescued by glycemic control. However, dysregulation of oxidative phosphorylation and reactive oxygen species persisted even after normalization of hyperglycemia. Notably, mRNA sequencing revealed that dysregulated proteins in the oxidative phosphorylation pathway were not accompanied by coordinated changes in mRNA levels, indicating post‐transcriptional regulation. Moreover, literature review and bioinformatics analysis suggested that hyperglycemia‐induced persistent alterations of miRNAs targeted genes from the persistently dysregulated oxidative phosphorylation pathway, whereas, oxidative phosphorylation dysfunction‐induced ROS regulated miRNA expression, which thereby might sustained the dysregulation of miRNAs. Conclusions: Glycemic control cannot rescue hyperglycemia‐induced alterations of subcellular proteins in the diabetic heart, and persistently altered proteins are involved in multiple functional pathways, including oxidative phosphorylation. These findings might provide novel insights into hyperglycemic memory in diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated that diabetes mellitus can increase the risk of cardiovascular disease and remains the principal cause of death in these patients. Costameres connect the sarcolemma with the cytoskeleton and extracellular matrix, facilitating the transmission of mechanical forces and cell signaling. They are related to cardiac physiology because individual cardiac cells are connected by intercalated discs that synchronize muscle contraction. Diabetes impacts the nanomechanical properties of cardiomyocytes, resulting in increased cellular and left ventricular stiffness, as evidenced in clinical studies of these patients. The question of whether costameric proteins are affected by diabetes in the heart has not been studied. This work analyzes whether type 1 diabetes mellitus (T1DM) modifies the costameric proteins and coincidentally changes the cellular mechanics in the same cardiomyocytes. The samples were analyzed by immunotechniques using laser confocal microscopy. Significant statistical differences were found in the spatial arrangement of the costameric proteins. However, these differences are not due to their expression. Atomic force microscopy was used to compare intrinsic cellular stiffness between diabetic and normal cardiomyocytes and obtain the first elasticity map sections of diabetic living cardiomyocytes. Data obtained demonstrated that diabetic cardiomyocytes had higher stiffness than control. The present work shows experimental evidence that intracellular changes related to cell-cell and cell-extracellular matrix communication occur, which could be related to cardiac pathogenic mechanisms. These changes could contribute to alterations in the mechanical and electrical properties of cardiomyocytes and, consequently, to diabetic cardiomyopathy. NEW & NOTEWORTHY: The structural organization of cardiomyocyte proteins is critical for their efficient functioning as a contractile unit in the heart. This work shows that diabetes mellitus induces significant changes in the spatial organization of costamere proteins, t tubules, and intercalated discs. We obtained the first elasticity map sections of living diabetic cardiomyocytes. The results show statistical differences in the map sections of diabetic and control cardiomyocytes, with diabetic cardiomyocytes being stiffer than normal ones. [ABSTRACT FROM AUTHOR]

Aims: Diastolic dysfunction represents the earliest and most common manifestation of diabetic cardiomyopathy. Nitric oxide (NO), a potent vasodilator and anti-inflammatory mediator released from the subendocardial and coronary endothelium, favors left ventricular distensibility and relaxation. In type 2 diabetes (T2D), the NO bioavailability is reduced due to the oxidative stress and inflammatory state of the endothelium, because of chronic hyperglycemia. The aim of the present research is to evaluate the relationship between endothelial function and diastolic function in subjects with T2D. Method: Subjects with T2D and age and sex-matched healthy controls were consecutively recruited. All participants underwent flow-mediated dilation (FMD) to assess endothelial function, and echocardiography to evaluate diastolic function. Results: Thirty-five patients (6 women, 29 men) and 35 healthy controls were included in the final analysis. FMD was significantly lower in T2D than controls (4.4 ± 3.4 vs. 8.5 ± 4.3%, p = 0.001). T2D presented different abnormalities in diastolic function compared to controls: lower E/A (early to late diastolic transmitral flow velocity), lower septal and lateral e′ (early diastolic myocardial tissue velocity at septum and lateral wall), and higher E/e′ (surrogate of filling pressure). In subjects with T2D, we observed a significant correlation between FMD and E/e′ (r = −0.63, p = 0.001), lateral e′ (r = 0.44, p = 0.03), and septal e′ (r = 0.39, p = 0.05). Conclusions: Our observational study demonstrated a link between FMD and diastolic dysfunction in subjects with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 2 diabetes mellitus, and its mechanisms are complex and poorly understood. Despite growing evidence suggesting that ferroptosis plays a significant role in cardiovascular disease, it has been less extensively studied in DCM. Fibroblast growth factor 21 (FGF21), whose mechanism of action is closely related to ferroptosis, is widely utilized in studies focused on the prevention and treatment of glucolipid metabolism-related diseases and cardiovascular diseases. Objective: To confirm the significant role of ferroptosis in DCM and to investigate whether FGF21 improves DCM by inhibiting ferroptosis and elucidating its specific molecular mechanisms. Methods: The animal DCM models were established through high-fat feeding combined with streptozotocin injection in C57BL/6J mice or by db/db mice, and the diabetic cardiomyocyte injury model was created using high glucose and high fat (HG/HF) culture of primary cardiomyocytes. Intervention modeling of FGF21 were performed by injecting adeno-associated virus 9-FGF21 in mice and transfecting FGF21 siRNA or overexpression plasmid in primary cardiomyocytes. Results: The findings indicated that ferroptosis was exacerbated and played a significant role in DCM. The overexpression of FGF21 inhibited ferroptosis and improved cardiac injury and function, whereas the knockdown of FGF21 aggravated ferroptosis and cardiac injury and function in DCM. Furthermore, we discovered that FGF21 inhibited ferroptosis in DCM by directly acting on ferritin and prolonging its half-life. Specifically, FGF21 binded to the heavy and light chains of ferritin, thereby reducing its excessive degradation in the proteasome and lysosomal-autophagy pathways in DCM. Additionally, activating transcription factor 4 (ATF4) served as the upstream regulator of FGF21 in DCM. Conclusions: The ATF4-FGF21-ferritin axis mediates the protective effects in DCM through the ferroptosis pathway and represents a potential therapeutic target for DCM. [ABSTRACT FROM AUTHOR]

• Hemp seed oil contains Cannabidiol, Dronabinol, and Cannabinol, as identified by GC–MS analysis. • MTT assay confirms Hemp seed oil's non-cytotoxic effect on L929 cells, ensuring cellular safety. • CAM assay showed inhibition of neovascularization patterns. • Docking studies revealed Hemp seed oil's capacity to inhibit early inflammatory cytokines. • Hemp seed oil emerges as effective herbal remedy for diabetic cardiomyopathy management. Present study was to assess the potential cytotoxic effects of commercially available Hemp seed oil and the effectiveness of its compounds in inhibiting inflammatory markers associated with diabetic cardiomyopathy. The bioactive components of Hemp seed oil were analysed using gas chromatography coupled with mass spectrometry (GC–MS). To evaluate the oil's cytotoxic properties, a modified 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium (MTT) assay was conducted on L929 cells (a mouse fibroblast cell line). Furthermore, an in vivo antiangiogenic assessment of the oil was performed using the chick chorioallantoic membrane (CAM) model, following a laboratory-standardized protocol. Docking and simulation studies were carried out to examine the binding and stability of the oil's compounds with inflammatory markers relevant to diabetic cardiomyopathy. The GC–MS analysis revealed that hemp seed oil contains several compounds, including Cannabidiol, Benzenemethanaminium, Dronabinol, Cannabinol, and Squalene. The cytotoxicity assessment on L929 cells demonstrated that Hemp seed oil did not exhibit any harmful effects at a concentration of 2.5 - 5 mg/mL. The CAM model confirmed the presence of antiangiogenic properties in Hemp seed oil, as evidenced by the inhibition of vascular patterns and blood vessel dissolution in the eggs. Additionally, docking and molecular dynamics (MD) simulations indicated that Benzenemethanaminium and Cannabielsoin exhibited the highest inhibitory efficacy and stability when interacting with IL-1β and C-reactive protein, respectively. This study suggests that Hemp seed oil possesses anti-inflammatory and anti-angiogenic properties, making it a potential herbal remedy for patients with diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Myocardial structural and functional abnormalities are hallmarks of diabetic cardiomyopathy (DCM), a chronic consequence of diabetes mellitus (DM). Maternal DM affects and increases the risk of heart defects in diabetic mothers compared with nondiabetic mothers. Momordica charantia exhibits antidiabetic effects due to various bioactive compounds that are phytochemicals, a broad group that includes phenolic compounds, alkaloids, proteins, steroids, inorganic compounds, and lipids. Pregnant maternal rats were split into four groups: control (C), M. charantia‐treated (MC), type 2 diabetes mellitus (T2DM) (DM), and diabetic (MC + DM) groups. Diabetes mothers had increased serum glucose, insulin, total cholesterol, triglyceride, and low‐density lipoprotein cholesterol levels and reduced high‐density lipoprotein cholesterol levels. Cardiac biomarkers such as cardiac troponin T (cTnT), creatine kinase‐myocardial band (CK‐MB), and lactate dehydrogenase were increased. Hormone levels of follicle‐stimulating hormone, luteinizing hormone, progesterone, and estrogen decreased significantly. Inflammatory markers such as interleukin 6 (IL‐6), tumor necrosis factor‐alpha (TNF‐α), and vascular adhesion molecule‐1 (VCAM‐1) were elevated in diabetic mothers. Oxidative stress markers indicated increased malondialdehyde and nitric oxide levels, while antioxidants such as glutathione, superoxide dismutase, and catalase were decreased in maternal heart tissue. The levels of apoptotic markers such as tumor suppressor 53 (P53) and cysteine aspartic protease‐3 (caspase‐3) were significantly greater in diabetic maternal heart tissue. Histopathological analysis revealed heart tissue abnormalities in diabetic maternal rats. M. charantia extract improved maternal diabetes‐induced changes in inflammation, antioxidant levels, and heart tissue structure. Research Highlights: Diabetes is characterized by a malfunction of glucose metabolism.Gestational diabetes increases maternal and fetal complications.Cardiovascular defects are linked to maternal gestational diabetes.Momordica charantia has antidiabetic effects on pregnant rats. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the mechanism of EMP1 action in high glucose (HG)‐induced H9c2 cardiac cell pyroptosis and oxidative injury. Rat cardiomyocytes H9c2 were exposed to 33 mM glucose for 24, 48, or 72 h to induce cytotoxicity. EMP1‐siRNA, NLRP3 agonist Nigericin, and pcNDA‐RAS were used to treat H9c2 cells under HG conditions. Cell Counting Kit (CCK)‐8 assay showed that cell proliferation was decreased following HG induction, which was rescued by EMP1 knockdown. Our results also suggested that EMP1 siRNA transfection significantly decreased the apoptosis and pyroptosis of HG‐induced cells, as indicated by the reduction of NLRP3 IL‐1β, ASC, GSDMD, cleaved‐caspase1 and cleaved‐caspase3 levels in HG‐induced H9c2 cells. In addition, EMP1 knockdown alleviated HG‐induced mitochondrial damage and oxidative stress in H9c2 cells. NLRP3 activation reversed the inhibitory effects of EMP1 knockdown on pyroptosis and oxidative stress in HG‐induced H9c2 cells. Mechanistically, we found that EMP1 knockdown suppressed the RAS/RAF/MAPK signaling pathway in HG‐induced H9c2 cells. RAS overexpression blocked the protective effect of EMP1 knockdown on HG‐induced H9c2 cell apoptosis, pyroptosis, and oxidative injury. Our findings suggest that EMP1 knockdown treatment might provide a novel therapy for diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

In the genesis and progression of cardiovascular and metabolic diseases (CVMDs), adipose tissue plays a pivotal and dual role. Complement factor D (CFD, also known as adipsin), which is mainly produced by adipocytes, is the rate-limiting enzyme of the alternative pathway. Abnormalities in CFD generation or function lead to aberrant immune responses and energy metabolism. A large number of studies have revealed that CFD is associated with CVMDs. Herein, we will review the current studies on the function and mechanism of CFD in CVMDs such as hypertension, coronary heart disease, ischemia/reperfusion injury, heart failure, arrhythmia, aortic aneurysm, obesity, insulin resistance, and diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Diabetes and its complications are major diseases that affect human health. Diabetic cardiovascular complications such as cardiovascular diseases (CVDs) are the major complications of diabetes, which are associated with the loss of cardiovascular cells. Pathogenically the role of ferroptosis, an iron-dependent cell death, and cuproptosis, a copper-dependent cell death has recently been receiving attention for the pathogenesis of diabetes and its cardiovascular complications. How exposure to environmental metals affects these two metal-dependent cell deaths in cardiovascular pathogenesis under diabetic and nondiabetic conditions remains largely unknown. As an omnipresent environmental metal, cadmium exposure can cause oxidative stress in the diabetic cardiomyocytes, leading to iron accumulation, glutathione depletion, lipid peroxidation, and finally exacerbate ferroptosis and disrupt the cardiac. Moreover, cadmium-induced hyperglycemia can enhance the circulation of advanced glycation end products (AGEs). Excessive AGEs in diabetes promote the upregulation of copper importer solute carrier family 31 member 1 through activating transcription factor 3/transcription factor PU.1, thereby increasing intracellular Cu+ accumulation in cardiomyocytes and disturbing Cu+ homeostasis, leading to a decline of Fe-S cluster protein and reactive oxygen species accumulation in cardiomyocytes mitochondria. In this review, we summarize the available evidence and the most recent advances exploring the underlying mechanisms of ferroptosis and cuproptosis in CVDs and diabetic cardiovascular complications, to provide critical perspectives on the potential pathogenic roles of ferroptosis and cuproptosis in cadmium-induced or exacerbated cardiovascular complications in diabetic individuals. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure with preserved ejection fraction and cardiac arrhythmias. Precursors of these complications, such as diabetic cardiomyopathy, remain incompletely understood and underdiagnosed. Detection of early signs of cardiac deterioration in T2DM patients is critical for prevention. Our goal is to quantify T2DM-driven abnormalities in ECG and cardiac imaging biomarkers leading to cardiovascular disease. Methods: We quantified ECG and cardiac magnetic resonance imaging biomarkers in two matched cohorts of 1781 UK Biobank participants, with and without T2DM, and no diagnosed cardiovascular disease at the time of assessment. We performed a pair-matched cross-sectional study to compare cardiac biomarkers in both cohorts, and examined the association between T2DM and these biomarkers. We built multivariate multiple linear regression models sequentially adjusted for socio-demographic, lifestyle, and clinical covariates. Results: Participants with T2DM had a higher resting heart rate (66 vs. 61 beats per minute, p < 0.001), longer QTc interval (424 vs. 420ms, p < 0.001), reduced T wave amplitude (0.33 vs. 0.37mV, p < 0.001), lower stroke volume (72 vs. 78ml, p < 0.001) and thicker left ventricular wall (6.1 vs. 5.9mm, p < 0.001) despite a decreased Sokolow-Lyon index (19.1 vs. 20.2mm, p < 0.001). T2DM was independently associated with higher heart rate (beta = 3.11, 95% CI = [2.11,4.10], p < 0.001), lower stroke volume (beta = −4.11, 95% CI = [−6.03, −2.19], p < 0.001) and higher left ventricular wall thickness (beta = 0.133, 95% CI = [0.081,0.186], p < 0.001). Trends were consistent in subgroups of different sex, age and body mass index. Fewer significant differences were observed in participants of non-white ethnic background. QRS duration and Sokolow-Lyon index showed a positive association with the development of cardiovascular disease in cohorts with and without T2DM, respectively. A higher left ventricular mass and wall thickness were associated with cardiovascular outcomes in both groups. Conclusion: T2DM prior to cardiovascular disease was linked with a higher heart rate, QTc prolongation, T wave amplitude reduction, as well as lower stroke volume and increased left ventricular wall thickness. Increased QRS duration and left ventricular wall thickness and mass were most strongly associated with future cardiovascular disease. Although subclinical, these changes may indicate the presence of autonomic dysfunction and diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function, while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryl iodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury, although its impact on diabetic cardiomyopathy remains elusive. Methods: Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanisms involved. Adult mice were made diabetic using streptozotocin (STZ, 50 mg/kg, i.p., for 5 days) while receiving UCF101 (7.15 mg/kg, i.p.). Results: STZ evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin 1, elevated p62), mitophagy (FUNDC1 and Parkin with upregulated TOM20), increased left ventricular end systolic diameter, reduced fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/re-lengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effects from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMP-activated protein kinase (AMPK) (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, the mitophagy inhibitor liensinine, and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C. Conclusion: These findings suggest that UCF101 rescues diabetes-mediated alterations in cardiac structure and function, likely through AMPK-mediated regulation of mitophagy. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac hypertrophy is a compensatory stress response produced by a variety of factors, and pathologic hypertrophy can lead to irreversible, severe cardiac disease. Glycosphingolipids (GSLs) are vital constituents of cells, and changes in their content and composition are important factors causing mitochondrial dysfunction in diabetic cardiomyopathy; however, the relationship between GSLs expression and cardiac hypertrophy and specific mechanisms associated with it are not clear. Methods: Here, using male C57BL/6 mice, we performed aortic arch reduction surgery to establish an animal model of pressure overload cardiac hypertrophy. In addition, phenylephrine was used in vitro to induce H9c2 cells and neonatal rat left ventricular myocytes (NRVMs) to establish a cellular hypertrophy model. Results: Mass spectrometry revealed that the composition of GSLs was altered in pressure overload-induced hypertrophied mouse hearts and in stimulated hypertrophied cardiomyocyte cell lines. Specifically, in both cases, the proportion of endogenous lactosylceramide (LacCer) was significantly higher than in controls. Inhibition of GSL synthesis with Genz-123346 in NRVMs reduced cell hypertrophy, as well as fibrosis and apoptosis. By Western blotting, we detected decreased intracellular expression of Sirt3 and elevated phosphorylation of JNK after phenylephrine stimulation, but this was reversed in cells pretreated with Genz-123346. Additionally, increased protein expression of FoxO3a and Parkin, along with a decreased LC3-II/I protein ratio in phenylephrine-stimulated cells (compared with unstimulated cells), indicated that the mitochondrial autophagy process was disrupted; again, pretreatment with Genz-123346 reversed that. Discussion: Our results revealed that changes in GSLs in cardiomyocytes, especially an increase of LacCer, may be a factor causing cellular hypertrophy, which can be alleviated by inhibition of GSLs synthesis. A possible mechanism is that GSLs inhibition increases the expression of Sirt3 protein, scavenges intracellular reactive oxygen species, and restores mitochondrial autophagy homeostasis, thereby lessening cardiomyocyte hypertrophy. In all, these results provide a new perspective for developing drugs for cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy （DCM） is a unique myocardial disease caused by diabetes mellitus, which can increase the risk of heart failure and death, and is one of the main causes of death of diabetes mellitus patients worldwide. Although the research on the pathogenesis of DCM has made great progress, it has not yet been fully clarified. Many studies have shown that long noncoding RNAs （lncRNAs） can interact with microRNAs （miRNAs） as competitive endogenous RNAs （ceRNAs）, participate in the regulation of gene expression, and then affect the development of DCM. This article gives an overview of lncRNAs and its biological functions as well as ceRNA hypothesis, and focuses on the role of lncRNAs as ceRNAs in regulating the occurrence and development of DCM. [ABSTRACT FROM AUTHOR]

Aims: Abnormalities in specific echocardiographic parameters and cardiac biomarkers have been reported among individuals with diabetes. However, a comprehensive characterization of diabetic cardiomyopathy (DbCM), a subclinical stage of myocardial abnormalities that precede the development of clinical heart failure (HF), is lacking. In this study, we developed and validated a machine learning‐based clustering approach to identify the high‐risk DbCM phenotype based on echocardiographic and cardiac biomarker parameters. Methods and results: Among individuals with diabetes from the Atherosclerosis Risk in Communities (ARIC) cohort who were free of cardiovascular disease and other potential aetiologies of cardiomyopathy (training, n = 1199), unsupervised hierarchical clustering was performed using echocardiographic parameters and cardiac biomarkers of neurohormonal stress and chronic myocardial injury (total 25 variables). The high‐risk DbCM phenotype was identified based on the incidence of HF on follow‐up. A deep neural network (DeepNN) classifier was developed to predict DbCM in the ARIC training cohort and validated in an external community‐based cohort (Cardiovascular Health Study [CHS]; n = 802) and an electronic health record (EHR) cohort (n = 5071). Clustering identified three phenogroups in the derivation cohort. Phenogroup‐3 (n = 324, 27% of the cohort) had significantly higher 5‐year HF incidence than other phenogroups (12.1% vs. 4.6% [phenogroup 2] vs. 3.1% [phenogroup 1]) and was identified as the high‐risk DbCM phenotype. The key echocardiographic predictors of high‐risk DbCM phenotype were higher NT‐proBNP levels, increased left ventricular mass and left atrial size, and worse diastolic function. In the CHS and University of Texas (UT) Southwestern EHR validation cohorts, the DeepNN classifier identified 16% and 29% of participants with DbCM, respectively. Participants with (vs. without) high‐risk DbCM phenotype in the external validation cohorts had a significantly higher incidence of HF (hazard ratio [95% confidence interval] 1.61 [1.18–2.19] in CHS and 1.34 [1.08–1.65] in the UT Southwestern EHR cohort). Conclusion: Machine learning‐based techniques may identify 16% to 29% of individuals with diabetes as having a high‐risk DbCM phenotype who may benefit from more aggressive implementation of HF preventive strategies. [ABSTRACT FROM AUTHOR]

Ischemic heart disease stands as the primary cause of mortality among diabetic patients. Despite advancements in vascular reconstruction and thrombolytic therapy that restore myocardial blood flow, these patients often experience poor cardiac function recovery and a higher mortality rate. This makes myocardial ischemia/reperfusion (I/R) injury a significant therapeutic challenge. Researches indicate that, under diabetic or obese conditions, adipocytes release extracellular vesicles (EVs) containing a variety of biomolecules, including RNA, proteins, adipocytokines, and mitochondria. These EVs play a pivotal role in maintaining systemic metabolic homeostasis. Importantly, adipocyte - derived EVs facilitate communication with diabetic hearts and play a regulatory role in myocardial I/R injury. This review summarizes recent studies on the modulatory effects of adipocyte ⁃derived EVs on diabetic myocardial I/R injury, highlighting potential underlying mechanisms. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, diabetic and obese patients experienced higher rates of hospital admissions, severe illness, and mortality. However, vaccinations failed to provide those vulnerable populations the same level of protection against COVID-19 severity as those without diabetic and obese phenotypes. Our study aimed to investigate how diabetes mellitus (DM) impacts the immune response following vaccination including the artificially designed trimeric SARS-CoV-2 spike (S)-protein. By using two diabetic mouse models, ob/ob mice (obese, hyperglycemic, and insulin-resistant) and STZ-treated mice (insulin-deficient and hyperglycemic), we observed a significant reduction in S-protein-specific IgG antibody titer post-vaccination in both diabetic models compared to wild-type (WT) mice. Both diabetic mouse models exhibited significant abnormalities in spleen tissue, including marked reductions in splenic weight and the size of the white pulp regions. Furthermore, the splenic T-cell and B-cell zones were notably diminished, suggesting an underlying immune dysfunction that could contribute to impaired antibody production. Notably, vaccination with the S-protein, when paired with an optimal adjuvant, did not exacerbate diabetic cardiomyopathy, blood glucose levels, or liver function, providing reassurance about the vaccine′s safety. These findings offer valuable insights into potential mechanisms responsible for the decreased persistence of antibody production in diabetic patients. [ABSTRACT FROM AUTHOR]

To assess the role of Cardiotrophin-1 (CT-1) and echocardiography in early detection of subclinical Diabetic Cardiomyopathy (DCM) in children with type 1 Diabetes Mellitus (T1D). This case-control study included two groups of children and adolescents aged between 7 and 18. Group (1) included forty patients with T1D (duration > 5 years) regularly followed at the children's hospital of Cairo University, and Group (2) included forty age and sex-matched healthy subjects as a control group. The serum level of CT-1 was measured, and conventional echocardiography, tissue Doppler imaging (TDI), and 2D speckle tracking echocardiography were performed. The level of CT-1 in the cases ranged from 11 to 1039.4 pg/ml with a median (IQR) of 19.4 (16.60–25.7) pg/ml, while its level in the control group ranged from 10.8 to 162.6 pg/ml with a median (IQR) of 20.2 (16.2–24.8) pg/ml. CT-1 levels showed no statistically significant difference between cases and controls. Patients had significantly higher mean left ventricle E/E′ ratio (p<0.001), lower mean 2D global longitudinal strain (GLS) of the left ventricle (LV) (p<0.001), and lower mean GLS of the right ventricle (RV) (p<0.001) compared to controls. Ofpatients with diabetes, 75 % had LV diastolic dysfunction, 85 % had RV diastolic dysfunction, 97.5 % had LV systolic dysfunction, and 100 % had RV systolic dysfunction. Non-conventional echocardiography is important for early perception of subclinical DCM in patients with T1D. CT-1 was not specific for early detection of DCM. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a serious common complication of diabetes. Unfortunately, there is no satisfied treatment for those patients and more studies are in critical need to cure them. Therefore, we aimed to carry out our current research to explore the role of two novel therapeutic approaches: one a biological drug aimed to block inflammatory signaling of the IL 1beta (IL1β) axis, namely, anakinra; the other is provision of anti-inflammatory regenerative stem cells. Wistar male rats were allocated into four groups: control group: type 2 diabetes mellitus (DM) induced by 6-week high-fat diet (HFD) followed by a single-dose streptozotocin (STZ) 35 mg/kg i.p., then rats were allocated into: DM: untreated; DM BM-MSCs: received a single dose of BM-MSCs (1 × 106 cell/rat) into rat tail vein; DM-Anak received Anak 0.5 μg/kg/day i.p. for 2 weeks. Both therapeutic approaches improved cardiac performance, fibrosis, and hypertrophy. In addition, blood glucose and insulin resistance decreased, while the antioxidant parameter, nuclear factor erythroid 2–related factor 2 (Nrf2) and interleukin 10 (IL10), and anti-inflammatory agent increased. Furthermore, there is a significant reduction in tumor necrosis factor alpha (TNFα), IL1β, caspase1, macrophage marker CD 11b, inducible nitric oxide synthase (iNOS), and T-cell marker CD 8. Both Anak and BM-MSCs effectively ameliorated inflammatory markers and cardiac performance as compared to non-treated diabetics. Improvement is mostly due to anti-inflammatory, antioxidant, anti-apoptotic properties, and regulation of TNFα/IL1β/caspase1 and Nrf2/IL10 pathways. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion injury (MIRI) is a major cause of cardiac death particularly in patients with diabetes. When the coronary artery is partially or completely blocked, restoration of blood perfusion can normally be achieved within a certain time due to the development of advanced techniques such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) surgery. However, cardiac tissue injury may aggravate progressively even after the ischemic myocardium is restored to normal perfusion. MIRI is often associated with various forms of cell death, including apoptosis, autophagy, programmed necrosis, pyroptosis, and ferroptosis, among others. Ferroptosis is known as iron-dependent cell death that is distinct from other programmed modes of cell death. Ferroptosis is under constitutive control by glutathione peroxidase 4 (GPX4), and the reduction of GPX4 may result in ferroptosis even if iron homeostasis is physiologically maintained. The essences of ferroptosis are substantial iron accumulation and lipid peroxidation that trigger cell death. Under impaired antioxidant system, cellular reactive oxygen species (ROS) accumulation leads to lipid peroxidation which consequently results in ferroptosis. Ferroptosis shares a few common features with several types of cell death and interplays with various forms of cell death such as autophagy and apoptosis in the development of cardiovascular diseases. More and more recent studies have demonstrated that ferroptosis plays an important role in MIRI. However, few studies have addressed the relative importance of ferroptosis in MIRI relative to other forms of cell deaths. In this review, we summarized the basic aspects and advances regarding the molecular pathogenesis of ferroptosis, evaluated its role in MIRI, and propose that the levels of ferroptosis may function as a major determinant of myocardial susceptibility to ischemia/reperfusion injury (IRI) in general and of the enhanced vulnerability to MIRI specifically in diabetes. [ABSTRACT FROM AUTHOR]

Objective: To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD). Methods: According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg·d)], medium-dose group [30 mg/(kg·d)], high-dose group [60 mg/(kg·d)], and nicorandil group [15 mg/(kg·d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot. Results: Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01). Conclusion: STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Background Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway. Methods To elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) administration, and AC16 human cardiomyocyte cell subjected to stimulation with high glucose (HG) and palmitic acid (PA). These models were employed to assess the changes in the senescence phenotype of cardiomyocytes and cardiac function following treatment with SGLT2i. Concurrently, we identified ANGPTL4, a key factor contributing to senescence in DCM, using RNA sequencing (RNA-seq) technology and bioinformatics methods. We further clarified ANGPTL4 role in promoting pathological aging of cardiomyocytes induced by hyperglycemia and hyperlipidemia through knockdown and overexpression of the factor, as well as analyzed the impact of SGLT2i intervention on ANGPTL4 expression. Additionally, we utilized chromatin immunoprecipitation followed by quantitative real-time PCR (ChIP-qPCR) to confirm that FOXO1 is essential for the transcriptional activation of ANGPTL4. Results The therapeutic intervention with SGLT2i alleviated the senescence phenotype in cardiomyocytes of the DCM mouse model constructed by high-fat feeding combined with STZ, as well as in the AC16 model stimulated by HG and PA, while also improving cardiac function in DCM mice. We observed that the knockdown of ANGPTL4, a key senescence-promoting factor in DCM identified through RNA-seq technology and bioinformatics, mitigated the senescence of cardiomyocytes, whereas overexpression of ANGPTL4 exacerbated it. Moreover, SGLT2i improved the senescence phenotype by suppressing the overexpression of ANGPTL4. In fact, we discovered that SGLT2i exert their effects by regulating the upstream transcription factor FOXO1 of ANGPTL4. Under conditions of hyperglycemia and hyperlipidemia, compared to the control group without FOXO1, the overexpression of FOXO1 in conjunction with SGLT2i intervention significantly reduced both ANGPTL4 mRNA and protein levels. This suggests that the FOXO1-ANGPTL4 axis may be a potential target for the cardioprotective effects of SGLT2i. Conclusions Collectively, our study demonstrates that SGLT2i ameliorate the pathological aging of cardiomyocytes induced by a high glucose and high fat metabolic milieu by regulating the interaction between FOXO1 and ANGPTL4, thereby suppressing the transcriptional synthesis of the latter, and consequently restoring cardiac function. Graphical abstract

Abstract Objectives The pathophysiology of diabetic cardiomyopathy (DCM) is a phenomenon of great interest, but its clinical problems have not yet been effectively addressed. Recently, the mechanism of ferroptosis in the pathophysiology of various diseases, including DCM, has attracted widespread attention. Here, we explored the role of PACS2 in ferroptosis in DCM through its downregulation of PACS2 expression. Methods and results Cardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues. Conclusions The PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.

Diabetes mellitus has surged in prevalence, emerging as a prominent epidemic and assuming a foremost position among prevalent medical disorders. Diabetes constitutes a pivotal risk element for cardiovascular maladies, with diabetic cardiomyopathy (DCM) standing out as a substantial complication encountered by individuals with diabetes. Apoptosis represents a physiological phenomenon observed throughout the aging and developmental stages, giving rise to the programmed cell death, which is implicated in DCM. Non-coding RNAs assume significant functions in modulation of gene expression. Their deviant expression of ncRNAs is implicated in overseeing diverse cellular attributes such as proliferation, apoptosis, and has been postulated to play a role in the progression of DCM. Notably, ncRNAs and the process of apoptosis can mutually influence and cooperate in shaping the destiny of human cardiac tissues. Therefore, the exploration of the interplay between apoptosis and non-coding RNAs holds paramount importance in the formulation of efficacious therapeutic and preventive approaches for managing DCM. In this review, we provide a comprehensive overview of the apoptotic signaling pathways relevant to DCM and subsequently delve into the reciprocal regulation between apoptosis and ncRNAs in DCM. These insights contribute to an enhanced comprehension of DCM and the development of therapeutic strategies.

Abstract Diabetic cardiomyopathy (DCM) is a severe cardiovascular complication of diabetes characterized by myocardial hypertrophy, fibrosis, and impaired cardiac function. Fibroblast growth factor 21 (FGF21) has emerged as a promising therapeutic target due to its antifibrotic, antioxidant, and anti-inflammatory properties. Our commentary summarizes and affirms the recent study by Wang et al., which demonstrates the significant role of ferroptosis in DCM pathogenesis. FGF21 has shown promise as a therapeutic target for DCM, potentially inhibiting ferroptosis, mitigating oxidative damage, and protecting cardiomyocyte function. Mechanistically, the study identified ATF4 as an upstream regulator of FGF21 in DCM, revealing that FGF21 directly interacts with ferritin and extends its half-life, thus inhibiting ferroptosis in DCM. These findings provide a theoretical basis for understanding the pathogenesis and treatment of DCM. Our commentary suggests that future studies should explore the role of non-cardiomyocyte cell types in DCM, verify findings with clinical samples, and address comprehensive methods for ferroptosis detection. Additionally, we discuss the clinical application and future potential of FGF21-based therapies for DCM. Such efforts may contribute to advancing DCM diagnosis and treatment, fostering the development of innovative therapeutic strategies.

Abstract Background Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A4 (LXA4), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA4 therapeutic treatment attenuates diabetes-induced cardiac pathology. Methods Six-week-old male apolipoprotein E-deficient (ApoE−/−) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot. Results As expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA1c) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control. Conclusions These findings demonstrated that LXA4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA4-based therapy for the management of diabetic heart disease. The recent development of stable LXA4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies. Graphical Abstract