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Background: Myocardial Infarction (MI) and severe mental disorders (SMDs) are two types of highly prevalent and complex disorders and seem to have a relatively high possibility of mortality. However, the contributions of common and rare genetic variants to their comorbidity arestill unclear. Methods: We conducted a combined genome-wide association study (GWAS) and exome-wide association study (EWAS) approach. Results: Using gene-based and gene-set association analyses based on the results of GWAS, we found the common genetic underpinnings of nine genes (GIGYF2, KCNJ13, PCCB, STAG1, HLA-C, HLA-B, FURIN, FES, and SMG6) and nine pathways significantly shared between MI and SMDs. Through Mendelian randomization analysis, we found that twenty-seven genes were potential causal genes for SMDs and MI. Based on the exome sequencing data of MI and SMDs patients from the UK Biobank, we found that MUC2 was exome-wide significant in the two diseases. The gene-set analyses of the exome-wide association study indicated that pathways related to insulin processing androgen catabolic process and angiotensin receptor binding may be involved in the comorbidity between SMDs and MI. We also found that six candidate genes were reported to interact with known therapeutic drugs based on the drug–gene interaction information in DGIdb. Conclusions: Altogether, this study revealed the overlap of common and rare genetic underpinning between SMDs and MI and may provide useful insights for their mechanism study and therapeutic investigations. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM), affecting over one-third of type 1 and nearly half of type 2 diabetes patients. As the leading cause of end-stage renal disease (ESRD) globally, DKD develops through a complex interplay of chronic hyperglycemia, oxidative stress, and inflammation. Early detection is crucial, with diagnosis based on persistent albuminuria and reduced estimated glomerular filtration rate (eGFR). Treatment strategies emphasize comprehensive management, including glycemic control, blood pressure regulation, and the use of nephroprotective agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Ongoing research explores novel therapies targeting molecular pathways and non-coding RNAs. Preventive measures focus on rigorous control of hyperglycemia and hypertension, aiming to mitigate disease progression. Despite therapeutic advances, DKD remains a leading cause of ESRD, highlighting the need for continued research to identify new biomarkers and innovative treatments. [ABSTRACT FROM AUTHOR]

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) down-regulates angiotensin-converting enzyme 2, potentially increasing angiotensin II. We hypothesized that losartan compared to usual care decreases mortality and is safe in patients hospitalized with coronavirus disease 2019 (COVID-19). We aimed to evaluate the effect of losartan versus usual care on 28-day mortality in patients hospitalized for acute COVID-19. Methods Eligibility criteria included adults admitted for acute COVID-19. Exclusion criteria were hypotension, hyperkalemia, acute kidney injury, and use of angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors within 7 days. Participants were randomized to losartan 25–100 mg/day orally for the hospital duration or 3 months or the control arm (usual care) in 29 hospitals in Canada and France. The primary outcome was 28-day mortality. Secondary outcomes were hospital mortality, organ support, and serious adverse events (SAEs). Results The trial was stopped early because of a serious safety concern with losartan. In 341 patients, any SAE and hypotension were significantly higher in the losartan versus usual care groups (any SAE: 39.8% vs 27.2%, respectively, P =.01; hypotension: 30.4% vs 15.3%, respectively, P <.001) in both ward and intensive care patients. The 28-day mortality did not differ between losartan (6.5%) versus usual care (5.9%) (odds ratio, 1.11 [95% confidence interval,.47–2.64]; P =.81), nor did organ dysfunction or secondary outcomes. Conclusions Caution is needed in deciding which patients to start or continue using ARBs in patients hospitalized with pneumonia to mitigate risk of hypotension, acute kidney injury, and other side effects. ARBs should not be added to care of patients hospitalized for acute COVID-19. Clinical Trials Registration NCT04606563. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1–7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes. NEW & NOTEWORTHY: The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function. [ABSTRACT FROM AUTHOR]

Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, with up to 40% of patients progressing to end-stage kidney disease (ESKD) within 30 years of diagnosis. IgAN is characterized by elevated serum levels of galactose- deficient IgA1 (Gd-IgA1), which leads to immune complex formation and deposition in the glomerular mesangium, causing kidney injury. A diverse disease course and the long-term follow-up required for clinically relevant endpoints (e.g., ESKD) have been barriers to the development of novel therapies in IgAN. Disease management has focused on supportive care with inhibitors of the renin-angiotensin system and, more recently, sodium-glucose transporter inhibitors to control proteinuria. The recent acceptance of proteinuria as a surrogate endpoint by regulatory bodies and a better understanding of disease pathology have helped to initiate the development of several novel treatments. Subsequently, a targeted-release formulation of budesonide and a dual endothelin/angiotensin inhibitor (sparsentan) have received accelerated approval for patients with IgAN. However, additional therapies are needed to target the different pathogenic mechanisms and individualize patient care. Several compounds currently under investigation target various effectors of pathology. There are promising clinical results from emerging compounds that target the generation of Gd-IgA1 by B cells, including inhibitors of A PRoliferation-Inducing Ligand (APRIL) and dual inhibitors of APRIL and B-cell activating factor (BAFF). Other investigational therapies target the complement cascade by inhibiting proteins of the lectin or alternative pathways. As the therapeutic landscape evolves, it will be important to revise treatment guidelines and develop updated standards of care. [ABSTRACT FROM AUTHOR]

Introduction: Hypertension is an important factor driving mortality among dialysis patients. Angiotensin-II receptor blocker (ARB) has been effective similarly to angiotensin-converting enzymes (ACEs) but with a low incidence of side effects. Methodology: The meta-analysis included all published studies that investigated the effect of ARB on the hypertension in adult dialysis patients (≥18 years). Data extraction was guided by a predetermined checklist. Data sources of the retrieved studies were PubMed, MEDLINE, ScienceDirect, SCOPUS, Cochrane, Web of knowledge, and Google Scholar were systematically searched until February 2023. Using the RevMan 5 software, the mean difference for systolic and diastolic BP (SBP and DBP) and the risk ratio (RR) of the adverse events (AEs) were pooled from the selected studies. The random-effects model was used to compare the difference in the pre-and post-dialysis of the SBP and DBP. Data analyses were performed from December 2022 to February 2023. The primary outcome was the reduction in SBP and DBP in dialysis hypertensive patients who were on anti-hypertensive agents, and the secondary outcome was assessment of AE associated with the drug after dialysis (PROSPERO Registration: CRD42022355369). Results: The initial search yielded 1,679 records, of which 84 studies underwent full-text evaluation, which identified 13 studies and 1,462 patients. The pooled standard MD for losartan with other anti- hypertensive agents, where the pre-dialysis SBP was 0.17 (95% confidence interval [CI]: -0.21-0.55) and the post-dialysis was 0.35 (95% CI: -0.17-1.02); yet, both are statistically non-significant, implies that there was no difference between Losartan and ARB drugs regarding the effect on the SBP. Diastolic BP for predialysis was -0.01 (95% CI: -0.65-0.63) and post-dialysis was 0.03 (95% CI: -0.24-0.30) and statistically non-significant. AEs by the ARB agents were lower compared to other anti-antihypertensive agents (relative risk [RR]: 1.01; 95% CI: 0.59-1.75) and statistically non-significant. Conclusion: This systematic review and meta-analysis of RCT demonstrated that ARB and other anti-hypertensive medications had similar impacts on the treatment of hypertension. [ABSTRACT FROM AUTHOR]

Gynecological cancers constitute a significant health burden for females worldwide, with cervical, endometrial and ovarian cancer being the most common types. The renin-angiotensin-aldosterone (RAA) system regulates blood pressure and is involved in various diseases, such as hypertension and heart failure. However, several studies have found that the angiotensin-1 receptor (AT1R) pathway is activated in various types of cancers, including breast, pancreatic and colorectal cancers. The AT1R receptor, in particular, has been shown to induce proliferation, neovascularization and fibrosis; therefore, its activation may induce cancer progression. Several epidemiological studies have found an association between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) with reduced cancer incidence; however, others have reported unclear or even deleterious associations between ARB use and cancers. These conflicting results necessitate the further exploration of the influence of the RAA system in the development of gynecological cancers. Several new factors in the RAA system have been identified, including angiotensin-(1-7) and angiotensin-(1-9), which have been shown to play a crucial role in preventing cell proliferation and, possibly, cancer progression. The present review discusses the association between the RAA system and gynecological cancers, specifically endometrial, ovarian and cervical cancers. [ABSTRACT FROM AUTHOR]

Objective: Apelin and visfatin are adipokines secreted from adipose tissue that play important roles in regulating blood pressure. Therefore, the current study aimed to investigate the effects of candesartan versus enalapril on apelin, visfatin, and lipid profiles in hypertensive patients. Methods: In this case-control study, 120 participants were enrolled in four groups; Healthy people, newly diagnosed hypertensive patients, and enalapril- and candesartan-treated patients. Results: Serum apelin levels were significantly lower and visfatin levels were significantly higher in newly diagnosed hypertensive patients compared with the control group (p=0.0015, p=0.0175 respectively). Moreover, apelin levels were higher and visfatin levels were lower in the candesartan-treated patients compared with the newly diagnosed group (p=0.0487, p<0.0001 respectively). Interestingly, apelin levels were non-significantly higher and visfatin levels were significantly lower in enalapril- treated patients compared with the newly diagnosed group (p<0.0001). Conclusions: Lower apelin and higher visfatin levels are associated with newly diagnosed patients with hypertension. Interestingly, the findings suggest that ACE inhibition and angiotensin receptor blockade by enalapril and candesartan, respectively, positively regulate apelin and visfatin levels in hypertension. Specifically, candesartan regulates these adipokine to a greater extent than enalapril. [ABSTRACT FROM AUTHOR]

Background The mechanism leading to the development of immunoglobulin A nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist, recently received accelerated approval in the USA for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. Methods Four-week-old gddY mice were given control chow, chow containing sparsentan or drinking water containing losartan until 12 or 20 weeks old. Results Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, endothelin type A receptor and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. Conclusions The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared with AT1R antagonism alone. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have investigated the potential influence of prior aspirin use on cardiac function in patients with ST-elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PPCI). However, the results from these studies have been conflicting. This study aimed to investigate whether prior aspirin use affects left ventricular (LV) function in these patients using echocardiography. Methods: The study included 260 consecutive STEMI patients, who were divided into two groups based on the presence or absence of prior aspirin use. Echocardiographic parameters, such as maximal left atrial (LA) size, LV ejection fraction (LVEF), early diastolic velocity (e'), E/A ratio, and E/e' ratio, were assessed within 72 hours of admission. Results: Aspirin users had an older age compared to non-users, as well as lower body mass index and renal function. They also had a greater history of hypertension and were more likely to be taking statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and calcium channel blockers. There were no significant differences in LVEF, maximal LA size, E/A ratio, E/e' ratio, and deceleration time between aspirin users and non-users. e' wave was marginally lower in aspirin users (P =0.054). After controlling for confounding variables, the previous use of aspirin did not show a significant impact. Conclusion: Prior aspirin use in STEMI patients does not have a significant impact on LV echocardiographic parameters. Our conclusions remained consistent even after adjusting for potential confounders. [ABSTRACT FROM AUTHOR]

aimegh1– 31Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia; 2Department of Pharmacy Practice, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 3Department of Research Office, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 4Department of Cardiology Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia; 5Department of Biostatistics and Bioinformatics, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 6Department of Saudi Biobank, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia Correspondence: Sultan Al Raddadi, Department of Pharmaceutical Care, King Abdulaziz Medical City-Riyadh, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia, Email [email protected] Background: Sacubitril/valsartan (S/V) is used in managing heart failure with reduced ejection fraction (HFrEF), reducing morbidity and mortality while improving symptoms and prognosis. This study aims to evaluate the effectiveness of S/V in patients with reduced left ventricular ejection fraction (LVEF) and its safety. Methods:  This retrospective cohort study included adult patients aged ≥ 18 years diagnosed with HFrEF, receiving S/V, and followed up at a tertiary hospital in Riyadh. Primary outcomes included improvements in LVEF on echocardiography and the number of hospitalizations due to acute decompensated heart failure (ADHF). Secondary outcomes assessed the safety profile of S/V. Multinomial logistic regression analysis was performed with statistical significance set at P < 0.05.  Results: The study included 107 patients: 80 with LVEF < 30% and 27 with LVEF 30– 40%. Six-month follow-up, LVEF improvement was categorized into three groups: no improvement, LVEF increased by 1 to < 10 points, and LVEF increased by ≥ 10 points. The LVEF was similar across groups (P = 0.59). Although hospitalizations due to ADHF were not significantly different between groups, they numerically decreased after initiating S/V (P = 0.1). S/V was generally well tolerated. Conclusion: This study suggests no significant benefit from S/V regarding LVEF improvement. It is recommended that heart failure clinics assess and titrate S/V to the maximum tolerated dose. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effect of dexamethasone (DXM) on acute lung and kidney injury with sepsis and its possible mechanism. Methods: Control (NC), lipopolysaccharide (LPS) and lipopolysaccharide + dexamethasone (LPS+DXM) treated groups were established by random assignment of 72 Wistar rats. The NC rats were injected with physiological saline, while the LPS group was injected with LPS (5 mg/kg) and LPS+DXM group was injected with LPS(5 mg/kg) first and followed by DXM (1 mg/kg). Serum tumor necrosis factor-α (TNF-α) and serum macrophage inflammatory protein 1α (MIP-1α) were measured by ELISA. Lung wet/dry weight ratio, serum creatinine(SCR) and blood urea nitrogen(BUN) were determined at various time points. Hematoxylin Eosin staining (HE) for pathological changes in the lung and kidney. Radioimmunoassay was used to detect the levels of angiotensin II (Ang II) in plasma, lung and kidney tissues. Immunohistochemistry and western blot (WB) were used to detect angiotensin II receptor type 1 (AT1R) protein and angiotensin II receptor type 2 (AT2R) protein in lung and kidney tissues. The level of nitric oxide (NO) in serum, lung and kidney were detected using nitrate reductase method. Results: Compared with control group, serum TNF-α, MIP-1α, SCR, BUN, lung W/D, Ang II level in plasma, lung and kidney, lung and kidney AT2R protein, NO level in serum, lung and kidney were significantly elevated(P<0.05) and pathological damage of lung and kidney tissues were showed in LPS group rats (P<0.05), whereas DXM down-regulated the above indexes and alleviate pathological damage of lung and kidney tissues. However, the expression of the lung and kidney AT1R protein was opposite to the above results. Conclusions: Sepsis can cause acute lung and kidney injury and changes RAAS components in circulating, lung and renal. DXM can improve acute lung and kidney injury in septic rats, and the mechanism may be related to the down-regulation of inflammatory factors, AngII, AT2R, NO and up-regulation of AT1R expression by DXM. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by growing incidence and poor outcomes. A large majority of HFpEF patients are cared by non‐cardiologists. The availability of sodium–glucose cotransporter 2 inhibitors (SGLT2i) as recommended therapy raises the importance of prompt and accurate identification and treatment of HFpEF across diverse healthcare settings. We evaluated HFpEF management across specialties through a survey targeting cardiologists, HF specialists, and non‐cardiologists.An independent web‐based survey was distributed globally between May and July 2023. We performed a post‐hoc analysis, comparing cardiologists, HF specialists, and non‐cardiologists. A total of 1460 physicians (61% male, median age 41[34–49]) from 95 countries completed the survey; 20% were HF specialists, 65% cardiologists, and 15% non‐cardiologists. Compared with HF specialists, non‐cardiologists and cardiologists were less likely to use natriuretic peptides (p = 0.003) and HFpEF scores (p = 0.004) for diagnosis, and were also less likely to have access to or consider specific echocardiographic parameters (p < 0.001) for identifying HFpEF. Diastolic stress tests were used in less than 30% of the cases, regardless of the specialty (p = 1.12). Multidrug treatment strategies were similar across different specialties. While SGLT2i and diuretics were the preferred drugs, angiotensin receptor blockers and angiotensin receptor–neprilysin inhibitors were the least frequently prescribed in all three groups. However, when constrained to choose one drug, the proportion of physicians favoring SGLT2i varied significantly among specialties (66% HF specialists, 52% cardiologists, 51% non‐cardiologists). Additionally, 10% of non‐cardiologists and 8% of cardiologists considered beta blocker the drug of choice for HFpEF.Significant differences among specialty groups were observed in HFpEF management, particularly in the diagnostic work‐up. Our results highlight a substantial risk of underdiagnosis and undertreatment of HFpEF patients, especially among non‐HF specialists. [ABSTRACT FROM AUTHOR]

Angiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. We investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. Acute administration of losartan significantly reduced participants' adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. This study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development. [ABSTRACT FROM AUTHOR]

Angiotensin II receptor blockers (ARBs) are contraindicated during pregnancy because of fetal toxicity. All previous reports on adverse fetal outcomes involved women who continued to take low‐dose ARBs for hypertension and were unaware of the adverse effects. Herein, we report the case of a 23‐year‐old pregnant woman in her third trimester who experienced an ARB overdose after an argument with her partner. Pregnancy was complicated by transient oligohydramnios, and fetal magnetic resonance imaging suggested renal failure. Despite these concerns, the newborn had no morphological abnormalities or abnormal neurological findings. Renal impairment improved over time, and the infant grew well. A single overdose of ARBs in the third trimester can lead to fetal renal failure, similar to long‐term low‐dose ARB administration; however, favorable outcomes are possible. An overdose of ARBs may transiently cause renal failure, which may improve. The study findings may inform counseling for women who are unexpectedly exposed to an overdose of ARBs. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this meta-analysis is to determine how sacubitril/valsartan (SV) compares to equivalent and sub-equivalent angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) in patients with heart failure with reduced ejection fraction (HFrEF). Methods: The databases of PubMed and EMBASE were used to identify those randomized controlled trials which compared SV to ARB/ACEI in patients with HFrEF. Only those trials that reported outcomes regarding total mortality, cardiovascular mortality, and worsening heart failure were considered. Meta-analysis was performed separately in those patients receiving equivalent doses of ARB/ACEI and those receiving sub-equivalent doses. Equivalent doses were SV 97/103 = valsartan 160 mg twice daily = enalapril 20 mg twice daily = ramipril 5 mg twice daily. Meta-analyses were performed using Review Manager 5.4. Results: Twelve randomized trials were identified involving 17,484 patients: 11,291 in the sub-equivalent group (8 trials) and 6193 in the equivalent group (4 trials). Meta-analyses showed there were no statistical differences regarding the outcomes of total mortality, cardiovascular mortality, and worsening heart failure in the equivalent dosing group. However, SV reduced total mortality (risk ratio (RR) = 0.85, 95% confidence interval (CI) = 0.78–0.93, p < 0.001), cardiovascular mortality (RR = 0.81, 95% CI = 0.73–0.90, p ≤ 0.001) and worsening heart failure (RR = 0.77, 95% CI = 0.64–0.92, p = 0.005) in the sub-equivalent group. Conclusion: When compared to equivalent doses of ARB/ACEI, SV is not superior in reducing mortality and worsening heart failure. SV is superior when compared to sub-equivalent doses of ACEI. [ABSTRACT FROM AUTHOR]

Background: Although guidelines recommend guideline‐directed medical therapy (GDMT) for patients with acute coronary syndrome (ACS), implementation is limited in clinical practice. Aim: To assess the level of GDMT in ACS patients after discharge who attended cardiac rehabilitation (CR) programs and association with clinical outcomes. Method: A cross‐sectional study was conducted in 13 rural and 10 metropolitan CR programs via all modes of delivery (face‐to‐face, telephone, or general practice‐hybrid) operating in South Australia, Australia. ACS patients were included if they were ≥18 years of age and were referred and attended CR programs with medication details recorded in their hospital discharge summary. GDMT was assessed according to the Australian clinical guidelines for the management of acute coronary syndromes 2016. Prescription of all the four recommended medication classes was considered optimal. Logistic regression and χ2 test were used for association. Ethical approval was granted by the South Australian Department for Health and Wellbeing Human Research Ethics Committee (Reference No. HREC/15/SAH/63) and the Northern Territory Department of Health Human Research Ethics Committee (Reference No. HREC 2015‐2484) which included a waiver of consent per the National Statement on Ethical Conduct in Human Research and the study conforms with the Good Clinical Practice Guidelines. Results: Of the 1229 patients included, 74.6% were male and 41.1% had acute myocardial infarction. Only 39.7% of patients received optimal prescription. Prescription of any three or two medication class combinations occurred for 78.3% and 94.1% of patients, respectively. Optimal GDMT was associated with fewer hospital admissions (odds ratio = 0.647, 95% confidence interval 0.424–0.987, p = 0.043) with no significant gender association. Women were less likely to be prescribed angiotensin converting enzyme inhibitors (p = 0.003), angiotensin receptor blockers (p = 0.007), statins (p = 0.005), and any two (p < 0.001) and three combinations (p = 0.023) of medication classes. Conclusion: GDMT prescription was suboptimal in patients with ACS before attendance at CR. Primary care and CR clinicians have missed an opportunity to implement best practice guideline recommendations, particularly for women. [ABSTRACT FROM AUTHOR]

Cancer therapy‐related cardiac dysfunction (CTRCD) is a complication of selected cancer therapy agents associated with decline in left ventricular ejection fraction (LVEF). Angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have established benefits in heart failure with reduced ejection fraction, but their efficacy for preventing CTRCD remains controversial. This narrative systematic review assessed the efficacy and safety of ACEI/ARB in the prevention of cancer therapy LVEF decline. We systematically searched PubMed, Embase and Cochrane from January 1980 to June 2022. Studies of interest were randomised controlled trials of patients with normal LVEF and active malignancy receiving cancer therapy, randomised to receive either an ACEI or ARB compared with a control group. The outcome was the change in LVEF from baseline to the end of the follow‐up period. Death, clinical heart failure and adverse drug reactions were recorded. A total of 3731 search records were screened and 12 studies were included, comprising a total of 1645 participants. Nine studies assessed the prevention of anthracycline‐induced LVEF decline, of which five showed a beneficial effect (1%–14% higher LVEF in treated groups), whereas four studies showed no effect. Three studies assessed the prevention of trastuzumab‐induced LVEF decline, of which one showed a beneficial effect (4% higher LVEF) in a subset of participants. There are mixed data regarding the efficacy of ACEI/ARB in preventing the LVEF decline in patients undergoing anthracycline or trastuzumab therapy, with evidence suggesting no clinically meaningful benefit observed in recent studies. [ABSTRACT FROM AUTHOR]

Essential hypertension can be treated with telmisartan, a strong, long-acting nonpeptide antagonist of angiotensin II type-1 (AT1) receptor. Without influencing other receptor systems involved in the regulation of the cardiovascular system, it specifically blocks the activation of the AT1 receptor by angiotensin II. When combined with high volume of distribution and telmisartan's distinctively high lipophilicity, the molecule provides the clinically significant benefit of strong tissue penetration. Additionally, it causes an increase in the protein level of adiponectin in adipocytes and activates peroxisome proliferatoractivated receptor c (PPAR-c). They might increase insulin sensitivity in this way. According to the BCS classification, it is class II medication because of its high permeability and low solubility. To increase the telmisartan solid dispersion's aqueous solubility and dissolution rate, various techniques were prepared and studied. One of the main issues with this medication is its low solubility in biological fluids, which leads to poor bioavailability after oral administration. Telmisartan's solubility was shown to be enhanced when the medication was dispersed solidly utilizing carrier such poly vinyl pyrrolidonek30, poly ethylene glycol 6000, βeta-cyclodextrin, Gelucire 43/01, Poloxamer 407, PVP K30 and HPMC E4, PEG 6000, and NaHCO3. [ABSTRACT FROM AUTHOR]

Renin-angiotensin system (RAS) modulators, including Angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI), are effective medications for controlling blood pressure. Cognitive deficits, including lack of concentration, memory loss, and confusion, were reported after COVID-19 infection. ARBs or ACEI increase the expression of angiotensin-converting enzyme-2 (ACE-2), a functional receptor that allows binding of SARS-CoV-2 spike protein for cellular invasion. To date, the association between the use of RAS modulators and the severity of COVID-19 cognitive dysfunction is still controversial. Purpose: This study addressed the following questions: 1) Does prior treatment with RAS modulator worsen COVID-19-induced cerebrovascular and cognitive dysfunction? 2) Can post-treatment with RAS modulator improve cognitive performance and cerebrovascular function following COVID-19? We hypothesize that pre-treatment exacerbates COVID-19-induced detrimental effects while post-treatment displays protective effects. Methods: Clinical study: Patients diagnosed with COVID-19 between May 2020 and December 2022 were identified through the electronic medical record system. Inclusion criteria comprised a documented medical history of hypertension treated with at least one antihypertensive medication. Subsequently, patients were categorized into two groups: those who had been prescribed ACEIs or ARBs before admission and those who had not received such treatment before admission. Each patient was evaluated on admission for signs of neurologic dysfunction. Pre-clinical study: Humanized ACE-2 transgenic knock-in mice received the SARS-CoV-2 spike protein via jugular vein injection for 2 weeks. One group had received Losartan (10 mg/kg), an ARB, in their drinking water for two weeks before the injection, while the other group began Losartan treatment after the spike protein injection. Cognitive functions, cerebral blood flow, and cerebrovascular density were determined in all experimental groups. Moreover, vascular inflammation and cell death were assessed. Results: Signs of neurological dysfunction were observed in 97 out of 177 patients (51%) taking ACEIs/ARBs prior to admission, compared to 32 out of 118 patients (27%) not receiving ACEI or ARBs. In animal studies, spike protein injection increased vascular inflammation, increased endothelial cell apoptosis, and reduced cerebrovascular density. In parallel, spike protein decreased cerebral blood flow and cognitive function. Our results showed that pretreatment with Losartan exacerbated these effects. However, post-treatment with Losartan prevented spike protein-induced vascular and neurological dysfunctions. Conclusion: Our clinical data showed that the use of RAS modulators before encountering COVID-19 can initially exacerbate vascular and neurological dysfunctions. Similar findings were demonstrated in the in-vivo experiments; however, the protective effects of targeting the RAS become apparent in the animal model when the treatment is initiated after spike protein injection. [ABSTRACT FROM AUTHOR]

Background. Kaempferol is a natural flavonoid with a wide range of pharmacological effects. The current study tested whether kaempferol prevents hypertension‐induced renal remodelling in rats. During the 5 weeks of experiments, rats (n = 7/group) were administered Nω‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME) (40 mg/kg/day) with either vehicle or kaempferol (20 mg/kg/day) or kaempferol (40 mg/kg/day) or lisinopril (5 mg/kg/day). Results. Kaempferol treatment alleviated haemodynamic changes occurring in hypertensive rats, including increases in systolic and diastolic blood pressure, pulse pressure, mean arterial pressure, and heart rate (p < 0.05). Kaempferol treatment prevented glomerular hypertrophy by reducing the increased glomerular cross‐sectional area, glomerular tuft area, Bowman's space area, glomerular volume, and the extent of renal tubulointerstitial fibrosis induced by hypertension (p < 0.05). Furthermore, animals in the L‐NAME group showed elevated angiotensin‐converting enzyme (ACE) activity and angiotensin II (Ang II) levels compared to those in the kaempferol‐treated group (p < 0.05). Kaempferol treatment also reverted the elevations in levels of superoxide anions and malondialdehyde and reduced catalase and superoxide dismutase activity in hypertensive rats (p < 0.05). L‐NAME‐treated rats showed overexpression of angiotensin II receptor type 1 (AT1), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), and matrix metalloproteinase‐9 (MMP‐9) proteins; conversely, the expression of these proteins was reduced in the kaempferol‐treated group (p < 0.05). Conclusion. Kaempferol treatment alleviated renal remodelling induced in rats by chronic hypertension. These mechanisms may be associated with the inhibition of ACE activity and suppression of the Ang II/AT1 receptor/NOX4/MMP‐9 cell signalling pathway in renal tissue. [ABSTRACT FROM AUTHOR]

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] μmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients. [ABSTRACT FROM AUTHOR]

Class A, rhodopsin‐like, G‐protein‐coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were believed to function as monomers, but a growing body of evidence has emerged to suggest that these receptors can function as homodimers and heterodimers and can undergo functional crosstalk to influence the actions of agonists or antagonists acting at each receptor. This review will focus on the angiotensin type 1 (AT1) and type 2 (AT2) receptors, as well as the relaxin family peptide receptor 1 (RXFP1), each of which have their unique characteristics but have been demonstrated to undergo some level of interaction when appropriately co‐expressed, which influences the function of each receptor. In particular, this receptor functional crosstalk will be discussed in the context of fibrosis, the tissue scarring that results from a failed wound‐healing response to injury, and which is a hallmark of chronic disease and related organ dysfunction. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc [ABSTRACT FROM AUTHOR]

Purpose Sacubitril/valsartan (SAC/VAL) or angiotensin receptor blockers (ARBs) are recommended therapy for heart failure with preserved ejection fraction (HFpEF), but little is known about their real-world comparative effectiveness among patients with HFpEF. The objective of this study was to determine the comparative effectiveness of SAC/VAL vs ARBs in preventing HF-related hospitalization or all-cause hospitalization among patients with HFpEF. Methods We conducted a cohort study using IBM MarketScan commercial and Medicare supplemental databases to identify patients aged 18 years or older with a diagnosis of HFpEF and initiation of SAC/VAL (2015-2020) or ARB (2009-2014) therapy. The index date was the date of the first SAC/VAL or ARB prescription fill. After propensity score (PS) matching with a ratio of 1 up to 3, Cox proportional hazards regression was used with robust variance estimators to compare the risks of HF-related hospitalization and all-cause hospitalization between the 2 therapies. Several subgroup and sensitivity analyses were conducted to check the robustness of the main analysis. Results After PS matching, 2,520 patients (846 receiving SAC/VAL and 1,674 receiving an ARB) were included in the final analyses. After controlling for covariates, there was no difference in the risk of HF-related hospitalization between SAC/VAL and ARB recipients (adjusted hazard ratio [aHR], 1.33; 95% confidence interval [CI], 0.99-1.77). There was also no difference in the risk of all-cause hospitalization between SAC/VAL and ARB recipients (aHR, 1.06; 95% CI, 0.91-1.24). Conclusion Among individuals with private or Medicare Advantage insurance plans, there was no significant difference in the risk of HF-related hospitalization or all-cause hospitalization between adults with HFpEF who received SAC/VAL and those who received ARB therapy. [ABSTRACT FROM AUTHOR]

Gastrodin, an anti‐inflammatory herbal agent, is known to suppress microglia activation. Here, we investigated whether it would exert a similar effect in reactive astrocytes and whether it might act through the renin‐angiotensin system (RAS) and sirtuin 3 (SIRT3). Angiotensinogen (ATO), angiotensin‐converting enzyme (ACE), angiotensin II type 1 (AT1) and type 2 (AT2) receptor and SIRT3 expression was detected in TNC‐1 astrocytes treated with BV‐2 microglia conditioned medium (CM) with or without gastrodin and lipopolysaccharide (LPS) pre‐treatment by RT‐PCR, immunofluorescence and western blotting analysis. Expression of C3 (A1 astrocyte marker), S100A10 (A2 astrocyte marker), proinflammatory cytokines and neurotrophic factors was then evaluated. The results showed a significant increase of ATO, ACE, AT1, SIRT3, C3, proinflammatory cytokines and neurotrophic factors expression in TNC‐1 astrocytes incubated in CM + LPS when compared with cells incubated in the CM, but AT2 and S100A10 expression was reduced. TNC‐1 astrocytes responded vigorously to BV‐2 CM treated with gastrodin + LPS as compared with the control. This was evident by the decreased expression of the abovementioned protein markers, except for AT2 and S100A10. Interestingly, SIRT3, IGF‐1 and BDNF expression was enhanced, suggesting that gastrodin inhibited the expression of RAS and proinflammatory mediators but promoted the expression of neurotrophic factors. And gastrodin regulated the phenotypic changes of astrocytes through AT1. Additionally, azilsartan (a specific inhibitor of AT1) inhibited the expression of C3 and S100A10, which remained unaffected in gastrodin and azilsartan combination treatment. These findings provide evidence that gastrodin may have a therapeutic effect via regulating RAS–SIRT3. [ABSTRACT FROM AUTHOR]

We hypothesized and investigated whether prenatal exposure to preeclampsia (PE) would simultaneously affect perinatal cardiovascular features and angiotensin system expressions. This prospective study was composed of mother-neonate dyads with (n = 49) and without maternal preeclampsia (n = 48) in a single tertiary medical center. The neonates exposed to PE had significantly larger relative sizes for the left and right coronary arteries and a higher cord plasma level of aminopeptidase-N, which positively correlated with the maternal diastolic blood pressures and determined the relative sizes of the left and right coronary arteries, whereas the encoding aminopeptidase-N (ANPEP) mRNA level in the PE cord blood leukocytes was significantly decreased, positively correlated with the neonatal systolic blood pressures (SBPs), and negatively correlated with the cord plasma-induced endothelial vascular cell adhesion molecule-1 mRNA levels. The PE cord plasma significantly induced higher endothelial mRNA levels of angiotensin II type 1 receptor (AT1R) and AT4R, whereas in the umbilical arteries, the protein expressions of AT2R and AT4R were significantly decreased in the PE group. The endothelial AT1R mRNA level positively determined the maternal SBPs, and the AT4R mRNA level positively determined the neonatal chamber size and cardiac output. In conclusion, PE may influence perinatal angiotensin system and cardiovascular manifestations of neonates across placentae. Intriguing correlations between these two warrant further mechanistic investigation. [ABSTRACT FROM AUTHOR]

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-β1–42 (Aβ1–42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aβ1–42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers. [ABSTRACT FROM AUTHOR]

Signaling of G protein-activated inwardly rectifying K+ (GIRK) channels is an important mechanism of the parasympathetic regulation of the heart rate and cardiac excitability. GIRK channels are inhibited during stimulation of Gq-coupled receptors (GqPCRs) by depletion of phosphatidyl-4,5-bisphosphate (PIP2) and/or channel phosphorylation by protein kinase C (PKC). The GqPCR-dependent modulation of GIRK currents in terms of specific PKC isoform activation was analyzed in voltage-clamp experiments in rat atrial myocytes and in CHO or HEK 293 cells. By using specific PKC inhibitors, we identified the receptor-activated PKC isoforms that contribute to phenylephrine- and angiotensin-induced GIRK channel inhibition. We demonstrate that the cPKC isoform PKCα significantly contributes to GIRK inhibition during stimulation of wildtype α1B-adrenergic receptors (α1B-ARs). Deletion of the α1B-AR serine residues S396 and S400 results in a preferential regulation of GIRK activity by PKCβ. As a novel finding, we report that the AT1-receptor-induced GIRK inhibition depends on the activation of the nPKC isoform PKCε whereas PKCα and PKCβ do not mainly participate in the angiotensin-mediated GIRK reduction. Expression of the dominant negative (DN) PKCε prolonged the onset of GIRK inhibition and significantly reduced AT1-R desensitization, indicating that PKCε regulates both GIRK channel activity and the strength of the receptor signal via a negative feedback mechanism. The serine residue S418 represents an important phosphorylation site for PKCε in the GIRK4 subunit. To analyze the functional impact of this PKC phosphorylation site for receptor-specific GIRK channel modulation, we monitored the activity of a phosphorylation-deficient (GIRK4 (S418A)) GIRK4 channel mutant during stimulation of α1B-ARs or AT1-receptors. Mutation of S418 did not impede α1B-AR-mediated GIRK inhibition, suggesting that S418 within the GIRK4 subunit is not subject to PKCα-induced phosphorylation. Furthermore, activation of angiotensin receptors induced pronounced GIRK4 (S418A) channel inhibition, excluding that this phosphorylation site contributes to the AT1-R-induced GIRK reduction. Instead, phosphorylation of S418 has a facilitative effect on GIRK activity that was abolished in the GIRK4 (S418A) mutant. To summarize, the present study shows that the receptor-dependent regulation of atrial GIRK channels is attributed to the GqPCR-specific activation of different PKC isoforms. Receptor-specific activated PKC isoforms target distinct phosphorylation sites within the GIRK4 subunit, resulting in differential regulation of GIRK channel activity with either facilitative or inhibitory effects on GIRK currents. [ABSTRACT FROM AUTHOR]

Telmisartan, a selective inhibitor of angiotensin II receptor type 1 (AT1), demonstrates nonlinear pharmacokinetics (PK) when orally administered in ascending doses to healthy volunteers, but the underlying mechanisms remain unclear. This study presents a physiologically based pharmacokinetic model integrated with target‐mediated drug disposition (TMDD‐PBPK model) to explore the mechanism of its nonlinear PK. We employed the Cluster‐Gauss Newton method for top‐down analysis, estimating the in vivo Km,OATP1B3 (Michaelis–Menten constant for telmisartan hepatic uptake via Organic Anion Transporting Polypeptide 1B3) to be 2.0–5.7 nM. This range is significantly lower than the reported in vitro value of 810 nM, obtained in 0.3% human serum albumin (HSA) conditions. Further validation was achieved through in vitro assessment in plated human hepatocytes with 4.5% HSA, showing a Km of 4.5 nM. These results underscore the importance of albumin‐mediated uptake effect for the hepatic uptake of telmisartan. Our TMDD‐PBPK model, developed through a "middle‐out" approach, underwent sensitivity analysis to identify key factors in the nonlinear PK of telmisartan. We found that the nonlinearity in the area under the concentration–time curve (AUC) and/or maximum concentration (Cmax) of telmisartan is sensitive to Km,OATP1B3 across all dosages. Additionally, the dissociation constant (Kd) for telmisartan binding to the AT1 receptor, along with its receptor abundance, notably influences PK at lower doses (below 20 mg). In conclusion, the nonlinear PK of telmisartan appears primarily driven by hepatic uptake saturation across all dose ranges and by AT1‐receptor binding saturation, notably at lower doses. [ABSTRACT FROM AUTHOR]

Cardiovascular Diseases (CVD) have claimed millions of lives, despite the efforts of medical professionals. There are several treatment methods for blocking a few neurohormonal cascades; however, it is debatable because there are few hypotheses, which claim that in Heart Failure (HF), these systems tend to activate potential counter-regulatory mechanisms. Angiotensin Receptor Neprilysin Inhibitors (ARNI) are developed to modulate both Renin-Angiotensi n-Aldosterone-System and Natriuretic Peptide, regulating neurohormonal cascade in HF. LCZ696 (Sacubitril/Valsartan) is the first-in-class ARNI, approved for managing HF. Initially, ARNI was developed to manage Hypertension, later the FDA regulatory label was expanded for the management of HF. Dapagliflozin belongs to the class of SGLT2 inhibitors that have shown potentially beneficial effects in HF. Would the two medications, which have distinct mechanisms of action but a similar effect-a decrease in the risk of HF-show additive or synergistic effects when taken together? India, known as "The Chronic Heart Disease Capital of the World", is accounting sharp rise in sudden cardiac death with young adults being the worst sufferers. This review inference that, using ARNI and Dapagliflozin together may have a larger positive effect on HF patients' quality of life by lowering their need for hospitalization due to HF deterioration. [ABSTRACT FROM AUTHOR]

Blood pressure and fluid balance are regulated hormonally by renin-angiotensin system (RAS). Influence on this system could be achieved by different compounds that act as angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers and renin inhibitors. The purpose of the present study is to predict the structures of the potent ACE inhibitors on the base of His-Leu peptide structural element of angiotensine I using computational methods. Different modifications were made in the structure of this dipeptide and the energy of binding with the enzyme were calculated. The docking results were analyzed and it was found that along with the important amino acid residue of the receptor molecule Arg167, the Tyr residues (35, 87, 88 and 92) as well as Cys180 are extremely important for the strong binding to the receptor and, accordingly, the manifestation of antagonistic action by the analogues. To block the receptor, the ligand molecule must have an intact terminal carboxyl group and an imidazole nucleus to participate in appropriate interactions. The inclusion of functional groups in the side chains of the amino acid residues of the dipeptide create an additional site for binding to the receptor. With the help of docking, the ligand molecule can be optimized, and this process is fast, saving the synthesis of many compounds and their biological testing. And finally, the most potent analogues will be synthesized and biologically tested. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a clinical syndrome characterized by structural and functional cardiac abnormalities. It is classified into three main phenotypes: HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). Objective: To evaluate the various phenotypes and treatment strategies for HF among a contemporary cohort of Egyptian patients. Patients and Methods: This cross-sectional, multi-center study was conducted on 510 HF patients at Al Nasr Hospital in Port Said over 12 months. Patients were grouped based on ejection fraction: HFrEF (43.2%), HFmrEF (23.3%), and HFpEF (33.5%). Data on demographics, comorbidities, medications, and non-pharmacological treatments were collected Results: Males were predominant in HFrEF (78.6%) while HFpEF was more common among females (35.1%, P < 0.01). Prior HF hospitalization was highest in HFrEF (89.5%, P < 0.001). HFrEF patients had lower eGFR (78 ±26 ml/min, P = 0.003), higher use of beta-blockers (P < 0.001) and angiotensin receptor neprilysin inhibitor (ARNI) (49.5%, P < 0.001), and more frequent revascularization. Sodium-glucose cotransporter 2 (SGLT2) inhibitors were underutilized due to cost (P < 0.001). Conclusion: HFrEF is more prevalent in males, while HFpEF is more common in females and associated with higher systolic blood pressure (SBP) and left ventricular hypertrophy (LVH). The significant underutilization of SGLT2 inhibitors and ARNI highlights the need for improved accessibility to advanced HF therapies in Egypt. Tailored management strategies are essential for optimizing care based on HF phenotypes. [ABSTRACT FROM AUTHOR]

Co-trimoxazole is a combination of two antimicrobial drugs, (trimethoprim and sulfamethoxazole), that are used to treat a wide variety of infections such as urinary tract infection, pneumocystis pneumonia and traveler's diarrhea. Hyperkalemia is a life-threatening electrolyte disturbance. Objectives: This study aimed to determine the incidence of hyperkalemia and its risk factors among hospitalized patients receiving intravenous co-trimoxazole at Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. Methods: This retrospective observational study included patients that were prescribed intravenous co-trimoxazole and identified using a computerized pharmacy system between January 2010 and December 2020. Patients' demographic and clinical characteristics were retrieved from their electronic medical records. The data were analyzed using descriptive and inferential statistical tests. Results: A total of 420 patients participated in this study. The median age of the patients was 51 (35-65) years and 55.5% were male. Hyperkalemia associated with co-trimoxazole was observed in (40.2%) of the patients. Around (44.2%) of patients who experienced hyperkalemia received a high dose of co-trimoxazole (15-20 mg/kg). Hyperkalemia occurred after the 5th day of co-trimoxazole treatment. Logistic regression analysis showed no relationship between hyperkalemia and age (adjusted odds ratio (AOR) 1.054, p=0.84), sex (AOR 1.167; p=0.471), dose (AOR 0.779; p=0.251), or use of concomitant medications (angiotensin-converting inhibitors, AOR 1.054, p=0.84; angiotensin receptor blockers, AOR 0.564; p=0.734; β-blockers, AOR 0.986; p=0.963; potassium supplements, AOR 0.59; p=0.175; nonsteroidal anti-inflammatory drugs, AOR 0.842, p=0.684; spironolactone AOR 0.748, p=0.629; heparin AOR 0.822, p=0.382; calcineurin inhibitor, AOR 1.537, p=0.406). Conclusion: Co-trimoxazole use was associated with a high incidence of hyperkalemia in this group of patients. No association between hyperkalemia and risk factors was observed. Serum potassium levels should be closely monitored, especially in the first week of co-trimoxazole treatment, to prevent the incidence of hyperkalemia, and clinical staff should adhere to serum monitoring guidelines. [ABSTRACT FROM AUTHOR]

This review article examines the mechanism of action of Angiotensin Receptor–Neprilysin Inhibitors (ARNIs) and Sodium–Glucose Co-Transporter 2 Inhibitors (SGLT2is) in managing chronic right ventricular (RV) dysfunction. Despite advancements in heart failure (HF) treatment, RV dysfunction remains a significant contributor to morbidity and mortality. This article explores the The article explores the impact of ARNIs and SGLT2is on RV function based on clinical and preclinical evidence, and the potential benefits of combined therapy. It highlights the need for further research to optimize patient outcomes and suggests that RV function should be considered in future clinical trials as part of risk stratification for HF therapies. This review underscores the importance of the early initiation of ARNIs and SGLT2is as per guideline-directed medical therapy for eligible HFrEF and HFpEF patients to improve co-existing RV dysfunction. [ABSTRACT FROM AUTHOR]

The cardiovascular continuum describes how several cardiovascular risk factors contribute to the development of atherothrombosis, ischemic heart disease, and peripheral arteriopathy, leading to cardiac and renal failure and ultimately death. Due to its multiple valences, the renin–angiotensin–aldosterone system plays an important role in all stages of the cardiovascular continuum, starting from a cluster of cardiovascular risk factors, and continuing with the development of atherosclerosis thorough various mechanisms, and culminating with heart failure. Therefore, this article aims to analyze how certain components of the renin–angiotensin–aldosterone system (converting enzymes, angiotensin, angiotensin receptors, and aldosterone) are involved in the underlying pathophysiology of the cardiovascular continuum and the possible arrest of its progression. [ABSTRACT FROM AUTHOR]

Objectives: Postoperative stiffness following arthroscopic rotator cuff repair (aRCR) is a major cause of morbidity reported in up to 23% of patients. Angiotensive converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), medications commonly used to treat hypertension, affect TGF-β, an essential regulator of both the inflammatory process and tissue healing that has been linked to the development of tissue fibrosis. Statins, a class of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have downstream cytokine effects thought to impact bone formation and resorption. The purpose of this study is to: determine if there is an association between ACEi, ARB, or statin usage and post-operative range of motion (ROM) following aRCR, determine if ACEi, ARB, or statin usage has any association with post-operative patient-reported outcome measures (PROMs) following aRCR, and to determine if ACEi, ARB, or statin usage has any association with the need for follow-up shoulder procedures following primary repair. Methods: This was an IRB approved retrospective cohort study examining all patients at a single institution undergoing primary aRCR from 1/1/2016 – 12/31/2019. Patients were identified by CPT codes and included if they had a minimum of 1-year postoperative follow-up and documented ROM outcomes. Patients with concomitant adhesive capsulitis, calcific tendinosis, glenohumeral arthritis, labral tears, prior history of shoulder surgery, previous history of humeral fractures, workman's compensation claims, age under 18, irreparable rotator cuff tear, history of substance abuse, or on dialysis were excluded. Patients were then separated into four groups based on usage of ACEi, ARBs, statins, or control. Demographic information, medication usage, concurrent diagnoses, and follow-up procedures were collected via chart review. Physician and physiotherapy notes were examined to determine ROM (flexion, abduction, internal rotation (IR), and external rotation (ER)) (Figure 1). PROMs were assessed through the American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation (SANE) and Simple Shoulder Test (SST). Results: After applying inclusion/exclusion criteria, 125 patients were included in the case group (ACEi 45 patients, ARB 27 patients, statins 53 patients) and 217 controls. No significant differences were found between groups with regard to demographics. Preoperatively, patients on ACEi or ARBs had significantly decreased active flexion (p=.022), IR (p=.002), and abduction (p<.001). Patients on statins had significantly decreased active abduction (85° vs. 130°, p=0.015), ER (40° vs. 50°, p=0.008), and IR (4 vs. 5, p=0.011). Postoperatively, patients on ACEi or ARBs had significantly decreased 6-month active ER (p=.015) that resolved by 12 months, and 6-month active abduction (p=.047) that also resolved by 12 months. Patients on statin medication had significantly increased 6-week active abduction (95° vs. 58°, p=0.017) that normalized to the control group by 3 month. All other ROM measurements at different time points were not significant. There was a significant decrease in postoperative SST scores in those taking ACEi or ARBs (p=.004), with no significance found in the other PROM scores at the 1-year mark. No significant differences were found in complications or reoperation rates between groups. Conclusions: Patients on ACEi or ARB medications are at an increased risk of decreased ROM before and 6 months after aRCR. Sub-analyses revealed that this effect was more pronounced with ACEi than with ARBs. Patients on statin medications are at an increased risk of decreased ROM before arthroscopic rotator cuff repair but increased ROM in the early postoperative period, especially abduction. Surgeons should use this information to guide patient education and rehabilitation perioperatively after arthroscopic rotator cuff repair. [ABSTRACT FROM AUTHOR]

This review delves into the most recent therapeutic approaches for pediatric chronic heart failure (HF) as proposed by the International Society for Heart and Lung Transplantation (ISHLT), which are not yet publicly available. The guideline proposes an exhaustive overview of the evolving pharmacological strategies that are transforming the management of HF in the pediatric population. The ISHLT guidelines recognize the scarcity of randomized clinical trials in children, leading to a predominance of consensus-based recommendations, designated as Level C evidence. This review article aims to shed light on the significant paradigm shifts in the proposed 2024 ISHLT guidelines for pediatric HF and their clinical ramifications for pediatric cardiology practitioners. Noteworthy advancements in the updated proposed guidelines include the endorsement of angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), and soluble guanylate cyclase (sGC) stimulators for treating chronic HF with reduced ejection fraction (HFrEF) in children. These cutting-edge treatments show potential for enhancing outcomes in pediatric HFrEF. Nonetheless, the challenge persists in validating the efficacy of therapies proven in adult HFrEF for the pediatric cohort. Furthermore, the proposed ISHLT guidelines address the pharmacological management of chronic HF with preserved ejection fraction (HFpEF) in children, marking a significant step forward in pediatric HF care. This review also discusses the future HF drugs in the pipeline, their mechanism of actions, potential uses, and side effects. [ABSTRACT FROM AUTHOR]

Background: Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin–angiotensin–aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons. Result: The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes. Conclusion: Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context. [ABSTRACT FROM AUTHOR]

The stabilization of different active conformations of G protein–coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (AT1R) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When AT1R endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor–β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor–β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V2 vasopressin receptor and a mutant β2-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds. Editor's summary: Biased agonists of GPCRs stimulate signaling through either G proteins or β-arrestins, which is clinically relevant if one pathway is therapeutic and the other produces side effects. Tóth et al. found that the endocytosis of the angiotensin II receptor AT1R and other GPCRs determined signaling strength through the β-arrestin pathway. Blocking endocytosis elicited responses from weak β-arrestin–biased agonists that resembled those generated by full agonists. As a result, ligand efficacy in β-arrestin signaling may be determined more by spatiotemporal regulation than by the induction of different receptor conformations at the plasma membrane by distinct agonists. These findings may guide the development of GPCR-targeting drugs that more effectively produce only the desired therapeutic response. —John F. Foley [ABSTRACT FROM AUTHOR]

Clinical treatment of acute myeloid leukemia (AML) largely relies on intensive chemotherapy. However, the application of chemotherapy is often hindered by cardiotoxicity. Patient sequence data revealed that angiotensin II receptor type 1 (AGTR1) is a shared target between AML and cardiovascular disease (CVD). We found that inhibiting AGTR1 sensitized AML to chemotherapy and protected the heart against chemotherapy-induced cardiotoxicity in a human AML cell–transplanted mouse model. These effects were regulated by the AGTR1-Notch1 axis in AML cells and cardiomyocytes from mice. In mouse cardiomyocytes, AGTR1 was hyperactivated by AML and chemotherapy. AML leukemogenesis increased the expression of the angiotensin-converting enzyme and led to increased production of angiotensin II, the ligand of AGTR1, in an MLL-AF9–driven AML mouse model. In this model, the AGTR1-Notch1 axis regulated a variety of genes involved with cell stemness and chemotherapy resistance. AML cell stemness was reduced after Agtr1a deletion in the mouse AML cell transplant model. Mechanistically, Agtr1a deletion decreased γ-secretase formation, which is required for transmembrane Notch1 cleavage and release of the Notch1 intracellular domain into the nucleus. Using multiomics, we identified AGTR1-Notch1 signaling downstream genes and found decreased binding between these gene sequences with Notch1 and chromatin enhancers, as well as increased binding with silencers. These findings describe an AML/CVD association that may be used to improve AML treatment. Editor's summary: Chemotherapy for acute myeloid leukemia (AML) can result in cardiotoxicity. Pan et al. found that the angiotensin II receptor type 1 (AGTR1) was increased in the blood from patients with AML or with cardiovascular disease and that it could be targeted to both enhance chemotherapy and protect against cardiotoxicity in mouse models. Genetic deletion of the receptor in a human AML cell transplant mouse model and in two other genetic mouse models of AML resulted in decreased leukemic burden and increased survival. Treating mice with losartan, an AGTR1 inhibitor, both enhanced the efficacy of chemotherapy against AML and prevented cardiotoxicity associated with the chemotherapy treatment. Together, these findings demonstrate that AGTR1 may be a target for improving AML treatment. —Brandon Berry [ABSTRACT FROM AUTHOR]

Background: Previous experimental and clinical studies suggested a beneficial effect of statins, metformin, angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers (RASi) on portal hypertension. Still, their effects on hard cirrhosis-related clinical endpoints, such as variceal bleeding and bleeding-related mortality, remain to be investigated. Methods: Thus, we recorded the use of statins, metformin and RASi in a large cohort of cirrhotic patients undergoing endoscopic band ligation (EBL) for primary (PP, n = 440) and secondary bleeding prophylaxis (SP, n = 480) between 01/2000 and 05/2020. Variceal (re-) bleeding and survival rates were compared between patients with vs. without these co-medications. Results: A total of 920 cirrhotic patients with varices were included. At first EBL, median MELD was 13 and 515 (56%) patients showed ascites. Statins, metformin and RASi were used by 49 (5.3%), 74 (8%), and 91 (9.9%) patients, respectively. MELD and platelet counts were similar in patients with and without the co-medications of interest. Rates of first variceal bleeding and variceal rebleeding at 2 years were 5.2% and 11.7%, respectively. Neither of the co-medications were associated with decreased first bleeding rates (log-rank tests in PP: statins p = 0.813, metformin p = 0.862, RASi p = 0.919) nor rebleeding rates (log-rank tests in SP: statin p = 0.113, metformin p = 0.348, RASi p = 0.273). Similar mortality rates were documented in patients with and without co-medications for PP (log-rank tests: statins p = 0.630, metformin p = 0.591, RASi p = 0.064) and for SP (statins p = 0.720, metformin p = 0.584, RASi p = 0.118). Conclusion: In clinical practice, variceal bleeding and mortality rates of cirrhotic patients were not reduced by co-medication with statins, metformin or RASi. Nevertheless, we recommend the use of these co-medications by indication, as they may still exert beneficial effects on non-bleeding complications in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock. Methods: In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65–75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin–angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples. Results: PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression. Conclusions: In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling. [ABSTRACT FROM AUTHOR]

Background: The PARADIGM HF trial showed sacubitril/valsartan (SV) to be superior to enalapril in patients with reduced ejection fraction (HFrEF). Since its publication, several other randomized trials have compared SV to either an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) in HFrEF which showed conflicting results regarding mortality, hospitalizations, and quality of life scoring. Objective: To review randomized comparative trials of SV to either ACEI or ARB in patients with HFrEF. Methods: PubMed and Embase databases were used to identify randomized comparative trials. The text terms sacubitril, angiotensin neprilysin, and LCZ696 were used for both searches. Meta-analysis, retrospective, adhoc, and cohort studies were excluded. Results: 1476 and 3983 citations were reviewed on PubMed and Embase, respectively. Of these, 11 randomized comparative trials to either ACEI or ARB were included for analysis. The mortality/quality of life benefits of SV over enalapril in the PARADIGM HF were not corroborated in any of the other trials. The effect of hospitalizations for heart failure was inconsistent among trials. Exercise tolerance was not improved with SV versus enalapril. Conclusion: The results of the PARADIGM HF trial have largely not been confirmed in subsequent randomized comparative trials. [ABSTRACT FROM AUTHOR]

An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs. [ABSTRACT FROM AUTHOR]

The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT1R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (<5%) in bioactivity, implicating a specialized function for this cluster. In contrast, angiotensin A (ARVYIHPF; AngA) has reduced bioactivity at AT1R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood–brain barrier more readily than bisartans, are the preferred drug candidates. [ABSTRACT FROM AUTHOR]

Background: Chronic neuroinflammation mediated by persistent microglial activation is strongly linked to neurodegeneration. Therefore, targeting microglial activation could be beneficial in treating neurodegenerative disorders. Angiotensin receptor blockers (ARBs), commonly prescribed for high blood pressure, exhibit prominent anti-inflammatory effects in the brain and are considered potential therapies for neurodegenerative diseases and neurotrauma. Although all ARBs are angiotensin II receptor type I antagonists, some ARBs act through other signaling pathways, allowing for multiple mechanisms of action. The anti-inflammatory mechanisms of ARBs are not well understood. Methods: In this study, we compared eight different FDA-approved ARBs for their ability to reduce the LPS stimulation of primary microglia or BV2 cells through analyses of nitric oxide production, reactive oxygen species generation, and the mRNA of proinflammatory cytokines. Finding specific and unique effects of telmisartan, we interrogated signaling pathways and other downstream effectors of telmisartan activity on microglia. Results: Our findings indicate that telmisartan showed the greatest efficacy in reducing the LPS induction of reactive oxygen species (ROS) and nitric oxide production in microglia. Uniquely amongst ARBs, telmisartan activated AMPK phosphorylation and inhibited mTOR phosphorylation. Telmisartan's anti-inflammatory activity was partially inhibited by the AMPK inhibitor compound C. Furthermore, telmisartan uniquely induced markers of autophagy in microglia through an AMPK–mTOR–autophagy pathway. Telmisartan also reduced microglial viability. Telmisartan's cytotoxicity was partially ameliorated by an autophagy inhibitor and a pan-caspase inhibitor, indicating a link between microglial autophagy and apoptosis. Conclusions: We conclude that telmisartan has unique properties relative to other ARBs, including potent anti-inflammatory actions and an induction of microglial autophagy, which may enable specific therapeutic uses. [ABSTRACT FROM AUTHOR]

Human iPSC-derived airway organoids (iPSC-AOs) exhibit cellular heterogenicity resembling the human native airway. Bioinformatics analysis revealed a robust dysregulation in inflammation, lipid-metabolism pathway, and alternative splicing in SARS-CoV-2 infected airway organoids. Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2), leading to the reduction of SARS-CoV-2 entry and replication. [Display omitted] • Single-cell RNA sequencing showed that iPSC-AOs exhibition of the genetic profiles highly resembling the genotypes of human airways. • iPSC-AOs are susceptible to SARS-COV-2 infection and the expressions of S and N proteins after viral infection. • Bioinformatics analysis indicated the involvement of aberrant enrichment of lipid transport and lipid pathways in infected iPSC-AOs. • Statin preincubation relocated ACE2, reduced N protein, and limited SARS-CoV-2 infection in iPSC-AOs. • Lipid modifications consistently inhibited viral entry of various SARS-CoV-2 strains (wild-type, alpha, delta, omicron). Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required. Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2). In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron. Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity‐associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein‐coupled receptor (MasR) and Mas‐related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity‐associated metabolic effects. [ABSTRACT FROM AUTHOR]

Background: The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1–7 has some promise in this regard. Objective: The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1–7. Methods: PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. Results: Angiotensin 1–7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1–7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1–7. Angiotensin 1–7 alleviates Ca2+ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1–7‐triggered cardiac tolerance to I/R. Furthermore, angiotensin 1–7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1–7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1–7 possesses anti‐inflammatory properties, possibly achieved through NF‐kB activity inhibition. Phosphoinositide 3‐kinase, Akt, and NO synthase are involved in the infarct‐reducing effect of angiotensin 1–7. However, the specific end‐effector of the cardioprotective impact of angiotensin 1–7 remains unknown. Conclusion: The molecular nature of the end‐effector of the infarct‐limiting effect of angiotensin 1–7 has not been elucidated. Perhaps, this end‐effector is the sarcolemmal KATP channel or the mitochondrial KATP channel. [ABSTRACT FROM AUTHOR]