Search Results (1,170)

The global burden of hypertension continues to rise, highlighting an urgent need for effective therapeutic strategies. Angiotensin-converting enzyme (ACE) is central to blood pressure regulation, but commonly used synthetic ACE inhibitors often have adverse side effects, spurring the search for safer natural alternatives. The aim of this study was to investigate Yanbian cattle hemoglobin as a novel precursor for ACE inhibitory peptides. The <1 kDa fraction was identified as exhibiting the highest inhibitory activity through the systematic screening of hydrolysates across multiple molecular weight ranges. LC-MS/MS analysis identified 1980 peptides, of which four were selected for further experiments. Solid-phase synthesis confirmed that NFGYDL exhibited the strongest ACE inhibition (IC₅₀ = 54.95 μM). Inhibition kinetics showed FHDYL acted as a mixed-type inhibitor, DLGHF and NFGYDL as competitive inhibitors and GFHLD as a non-competitive inhibitor. Molecular dynamics simulations validated the stable binding of these bovine blood-derived peptides to the ACE complex. HUVEC functional assays demonstrated that four peptides significantly increased angiotensin II-induced nitric oxide production and endothelin-1 levels, suggesting their potential antihypertensive activity. These findings suggested that bovine blood is a promising natural source of ACE-inhibitory peptides and holds potential for application as a functional component in functional foods targeting hypertension management. Full article

COVID-19 perturbs the renin-angiotensin system (RAAS) and inflammatory pathways, shaping disease severity. Soluble ACE2 (sACE2) and angiotensin II (Ang II) are central regulators of vascular and immune homeostasis. We profiled plasma from COVID-19 patients and controls using ELISA, together with 48 cytokine profiling and clinical data. Both sACE2 and Ang II were significantly elevated in patients. Increased Ang II was associated with oxygen supplementation and dyspnea, and negatively correlated with IL-3, whereas sACE2 correlated with IL-13 and FGF. Comorbidities modulated cytokine expression: diabetes mellitus was linked to reduced LIF and MCP-1, hypertension to decreased LIF and increased IP-10, and obesity to elevated IL-12p70. Age correlated with TNF and HGF, and reduced oxygen saturation was associated with lower LIF. These findings reveal that acute COVID-19 disrupts RAAS and amplifies immune dysregulation, with Ang II emerging as a pivotal mediator of respiratory compromise and inflammatory imbalance, underscoring its potential as a biomarker and therapeutic relevance. Full article

One of the most critical aspects of post-acute COVID-19 syndrome (PACS) and post-acute COVID-19 vaccination syndrome (PACVS) is the presence of autoantibodies. These autoantibodies are directed against various receptors in the autonomic and cardiovascular systems, including those targeting proteins of the renin–angiotensin system (RAS). The RAS plays a central role in regulating vascular homeostasis, inflammation, and endothelial function. During SARS-CoV-2 infection, the interaction of the spike (S) protein with angiotensin-converting enzyme 2 (ACE2) can alter the balance of the RAS, favoring an imbalance towards the ACE/Angiotensin II/AT1R axis, known for its pro-inflammatory, pro-thrombotic, and vasoconstrictive properties. Similar pathological mechanisms also come into play in response to vaccinations that use the S protein as an antigen. Studies conducted by other groups and us on patients with PACS and PACVS have revealed the presence of autoantibodies directed against these RAS components and the mechanisms by which these antibodies can worsen the clinical situation. In particular, anti-ACE2, presumably formed by the anti-idiotype network or molecular mimicry, is correlated with PACVS symptoms in many patients. Furthermore, the presence of anti-MAS1 antibodies can reduce the efficiency of the ACE2/Angiotensin-(1–7)/MAS1 axis, which normally acts as a counter-regulator. Considering this evidence, an analysis of RAS molecules and the autoantibodies implicated in reactions to them may be useful for evaluating a state of persistent dysregulation associated with post-vaccination symptoms such as asthenia, headache, skin edema and bruising, cardiovascular alterations, and neurovegetative manifestations. Finally, we offer insights into diagnosing these multifaceted syndromes and working hypotheses to guide research into possible therapeutic approaches. Full article

Background/Objectives: The renin–angiotensin–aldosterone (RAA) system is a key regulator of cardiovascular homeostasis. Recent evidence suggests that Angiotensin II (Ang II) can trigger ferroptosis, an iron-dependent form of cell death. We previously demonstrated that periodontitis induces neurovascular dysfunction, and our preliminary observations indicate that this oral inflammatory model is associated with elevated blood pressure. However, the mechanism by which Ang II impaired nitrergic vasodilation and triggered ferroptosis in cerebral arteries remains unclear. This study investigates the functional effects of electrical and chemical nerve stimulation in adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Methods: Endothelium-denuded basilar arterial (BA) rings from SHRs and WKYs were used to assess the impact of Ang II on neurogenic relaxation via wire myography. Results: Vascular relaxation responses to nicotine and transmural nerve stimulation (TNS) were significantly diminished in SHRs compared to WKYs. This impairment was reversed by both acute preincubation and chronic treatment with losartan (an AT1 receptor antagonist). In WKY BAs, exogenous Ang II pretreatment inhibited relaxation responses to nicotine, TNS, and isoproterenol. Importantly, this inhibition was effectively reversed by marimastat (MMP inhibitor), catalase (antioxidant), and ferrostatin-1 (ferroptosis inhibitor). Conclusions: Our findings indicate that Ang II induces functional alterations in neurovascular signaling patterns by triggering ferroptosis within nerve terminals. This process leads to a functional imbalance between sympathetic and parasympathetic influences, ultimately impairing neurogenic nitrergic dilation in the BAs of SHRs. These results suggest that targeting Ang II-induced ferroptosis may alleviate the neuroinflammation and cognitive decline associated with hypertension-related cerebrovascular dysfunction. Full article

Endocrine disorders are increasingly recognized as major contributors to secondary cardiomyopathies, leading to profound alterations in cardiac structure and function. This comprehensive review synthesizes current evidence on the genetic basis of cardiomyopathies associated with endocrine conditions, including primary aldosteronism, Cushing’s syndrome, pheochromocytoma/paraganglioma, acromegaly, thyroid disorders, hyperparathyroidism, and diabetic cardiomyopathy. We examine the contribution of somatic and germline mutations, genetic polymorphisms, shared molecular pathways transforming growth factor-β (TGF-β)/SMAD (TGF-β/SMAD signaling, the renin–angiotensin–aldosterone system, oxidative stress, and calcium handling), sarcomeric gene modifiers, ion channel variants, and epigenetic mechanisms to disease pathogenesis. We propose a conceptual framework distinguishing three major categories of genetic involvement: (i) variants causing the primary endocrinopathy; (ii) genetic modifiers of myocardial susceptibility under conditions of hormonal excess; and (iii) direct pleiotropic effects, whereby single gene variants independently cause both endocrine and cardiac phenotypes. In addition, we discuss genotype–phenotype correlations, ethnic and population differences in genetic susceptibility, the emerging role of polygenic risk scores, and precision medicine approaches. Overall, this review provides an integrated perspective on the complex genetic architecture of endocrine-related cardiomyopathies and outlines practical considerations for genetic testing aimed at improving patient management and clinical outcomes. Full article

Hypertension continues to be a major global public health challenge. Dopamine generated in the kidney is a vital coordinator of sodium homeostasis and blood pressure control. Dopamine exerts its effects by activating its receptors, which are divided into the D₁-like receptor family (D₁R and D₅R) and the D₂-like receptor family (D₂R, D₃R, and D₄R). All five dopamine receptor subtypes are differentially expressed along the nephron. Dopamine receptors inhibit the activities and/or expression of renal tubular sodium transporters/exchangers/channels, decrease renal oxidative stress, and interact with other receptors, including angiotensin II receptors. Many studies have demonstrated that renal dopamine receptors play an important role in the regulation of blood pressure. The germline deletion or renal-selective silencing of any of the five dopamine receptor subtypes may impair sodium excretion and increase blood pressure. In addition, renal dopamine receptor expression and/or function are regulated by some factors such as G protein-coupled receptor kinases, oxidative stress, and sorting nexins. In this article, we summarize the role of each dopamine receptor subtype in the pathogenesis of hypertension and discuss the potential regulatory mechanisms of their expression and function. These may lead to the development of novel therapeutic approaches to the prevention and treatment of hypertension. Full article

Background/Objective: Buccal delivery offers a potential route to circumvent gastrointestinal degradation and hepatic first-pass metabolism, but hydrophilic peptides typically exhibit limited mucosal permeation. Nanostructured lipid carriers (NLCs) have been proposed as delivery platforms capable of modulating interfacial interactions and improving mucosal transport. This study aimed to quantitatively evaluate the ex vivo buccal permeation of angiotensin II (Ang II), used as a hydrophilic peptide model, when associated with NLCs compared with free peptide under matched Franz diffusion cell conditions. Methods: Ang II-associated NLCs were prepared by melt emulsification combined with a low-energy injection technique. Particle size, polydispersity index, and zeta potential were determined by dynamic light scattering and laser Doppler electrophoresis. Association efficiency and drug loading were quantified by indirect spectrofluorometric analysis. Ex vivo permeation studies were conducted using porcine buccal mucosa mounted in Franz diffusion cells, and cumulative permeation, steady-state flux, and apparent permeability coefficients were calculated. Results: The NLCs exhibited nanometric size, moderate polydispersity, and association efficiency above 80%, and remained colloidally stable at 4 °C for 28 days. In ex vivo experiments, Ang II-associated NLCs showed measurable cumulative permeation, reaching approximately 9% after 2 h, whereas free Ang II was not detected in the receptor compartment under the tested conditions. Conclusions: This work provides a quantitative ex vivo buccal transport comparison of a hydrophilic peptide model delivered as NLC-associated versus free peptide under matched Franz cell conditions. The findings support further investigation of NLC-based approaches for buccal delivery of vasoactive peptides and provide a rational basis for future in vivo evaluation of mucosal delivery performance and systemic exposure. Full article

In patients, extraintestinal manifestations of inflammatory bowel disease (IBD) are attenuated ventricular contractile function and arrhythmia. To determine the mechanism of IBD-induced changes in ventricular function, we used a mouse model of dextran sodium sulfate (3.5% weight/volume; 7 days)-induced colitis. Changes in cardiac function were quantified in isolated ventricular myocytes (VM) by cell shortening, imaging of [Ca²⁺]_i, reactive oxygen species (ROS), and t-tubular density. During colitis, VMs exhibited attenuated cell-shortening and altered Ca²⁺-handling properties. A prolonged Ca²⁺ transient (CaT) rise time correlated with an increased coefficient of variation in the subcellular Ca²⁺ release and an attenuated t-tubular density. T-tubular loss was accompanied by increased ROS production, calpain-2 (CAPN2) expression, junctophilin-2 (JPH-2) cleavage, and autophagy. Inhibition of Angiotensin-converting enzyme during colitis (Perindopril: 3 mg/kg/day) prevented the increase in CAPN2, ROS production, autophagy, and t-tubular remodeling. It failed, however, to restore full length JPH-2. We conclude that, during IBD, the angiotensin II (AngII)-induced loss of t-tubular integrity and altered cellular Ca²⁺ handling can be prevented by suppression of the AngII-dependent increase in CAPN2 and autophagy and thus suppression of AngII signaling might benefit IBD patients with cardiac manifestations of the disease. Full article

Background: The pathophysiological mechanisms of Abdominal Aortic Aneurysm (AAA) are not elucidated. Alterations in mitochondrial function, such as a reduction in oxidative phosphorylation (OXPHOS), have been observed at genome level and functionally in vascular smooth muscle cells. Metformin reduces AAA development and growth in diabetic patients, but the precise mechanisms are not known. In this paper we aim to demonstrate the feasibility of measuring mitochondrial functional capacity ex vivo in intact murine aneurysmal tissue and confirm a decrease in OXPHOS, and to determine if the protective effect of metformin on AAA is mediated by mitochondrial function. Methods: AAA was induced in ApoE KO mice by administration of angII (1000 ng/kg/min) through osmotic minipumps. Metformin was administered in drinking water at a dose of 100 mg/kg/day. The abdominal aorta was isolated in situ and mitochondrial functional capacity was analyzed ex vivo in whole permeabilized tissue by high-resolution respirometry. Results: Mitochondrial respiration was successfully measured ex vivo in whole aneurysmal tissue. Mitochondrial function was impaired in angII-treated mice, with decreased fold change in Complex I and Complex I+II oxygen consumption, relative to basal levels. Complex II oxygen consumption was also decreased in angII-treated mice. Rescue treatment of mice with metformin did not affect or restore mitochondrial function. Conclusions: Mitochondrial function can be evaluated in murine whole aneurysmal tissue, providing a method for a physiological approach to the study of mitochondrial function in AAA. Mitochondrial function is impaired in AAA. However, rescue treatment with metformin is not sufficient to recover mitochondrial function and seems not to be the mechanism behind prevention of aneurysm. Full article

Autoantibodies (AAbs) play an important role in the development of autoimmune diseases. While many AAbs induce apoptosis of target cells, a distinct subgroup, termed functional autoantibodies (fAAbs) against G protein–coupled receptors (GPCRs), can modulate physiological receptor signaling without inducing cell death. The functional activity of GPCR-fAAbs may be influenced by various cofactors, including inflammation (e.g., inflammatory cytokine, ciliary neurotrophic factor (CNTF)) and ischemia. As ischemia triggers a substantial release of arachidonic acid (AA) from membrane phospholipids, the present study aimed to examine exploratively the influence of AA, eicosapentaenoic acid (EPA), and CNTF on the responses of spontaneously beating neonatal rat cardiomyocytes to GPCR agonists and GPCR-fAAbs. AA and EPA differentially influenced responses in cardiomyocytes induced by GPCR-fAAbs: AA altered the functional responses associated with adrenergic β₂-fAAb, adrenergic α₁-fAAb, angiotensin II (AT1)-fAAb, endothelin A (ETA)-fAAb and angiotensin 1–7 MAS-fAAbs. However, muscarinergic M₂-fAAb responses remained largely unaffected. In contrast, EPA attenuated the responses to β₂-fAAb, α₁-fAAb, AT1-fAAb, and ETA-fAAb, while MAS-fAAb and M₂-fAAb responses were not markedly altered. CNTF acted as a time-dependent modulator of cardiomyocyte chronotropic responses and influenced the magnitude of GPCR-mediated signaling on a cardiomyocyte bioassay. Together, these findings might suggest that lipid mediators such as AA and EPA or CNTF may modulate functional responses of cardiomyocytes associated with GPCR-fAAbs. Full article

Background: Abdominal aortic aneurysm (AAA) is a vascular disease with a high mortality rate upon rupture (85–90%). Surgical repair remains the most effective intervention, whereas pharmacological treatments to prevent aneurysm expansion or rupture are limited. Vascular smooth muscle cells (VSMCs) play a crucial role in AAA pathogenesis, and metabolic dysregulation is increasingly recognized as a contributor to disease progression. This study investigated metabolic changes in VSMCs and their association with AAA pathology using untargeted metabolomics. Methods: Angiotensin II (Ang II) was used to stimulate rat VSMCs and induce AAA in ApoE−/− mice. Untargeted metabolomic analysis was performed using liquid chromatography–tandem mass spectrometry to detect metabolite changes. Differential metabolites were identified using orthogonal partial least squares discriminant analysis, and metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes and metabolic set enrichment analysis. Results: In Ang II-treated VSMCs, 54 differential metabolites (24 upregulated; 30 downregulated) were identified, whereas 470 differential metabolites (206 upregulated; 264 downregulated) were detected in mouse aortas. Three metabolites—carnitine, lysophosphatidylcholine (0:0/20:4), and 5-hydroxyeicosatetraenoic acid—were common in both models and were enriched in bile secretion and tryptophan metabolism pathways. The carnitine–FXR signaling axis emerged as a potential therapeutic target. Conclusions: This study revealed Ang II-induced metabolic changes in VSMCs and their association with AAA pathology. The carnitine–FXR signaling axis may contribute to AAA development, providing new directions for diagnostic biomarkers and therapeutic targets. Future studies should validate these findings in human AAA samples to determine their clinical relevance. Full article

Cardiac fibrosis represents a final common pathway in a wide range of cardiac disorders, leading to structural remodeling, diastolic dysfunction, and heart failure. From a pathologist’s viewpoint, fibrotic remodeling displays distinctive morphologic patterns such as interstitial, perivascular, and replacement fibrosis, which mirror specific cellular and molecular mechanisms. Central to this process is the activation of cardiac fibroblasts into myofibroblasts, driven by profibrotic signaling cascades such as transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog proteins (SMAD), Wingless/Integrated signaling pathway (Wnt)/βeta-catenin, and Hippo-Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathways. Neurohumoral mediators, including angiotensin II and aldosterone, further amplify extracellular matrix synthesis and tissue stiffness. Epigenetic modulators and non-coding RNAs (n-c RNAs) orchestrate transcriptional programs that perpetuate fibroblast activation. Histopathological correlates of these molecular events, collagen deposition, alpha-smooth muscle actin (α-SMA) expression, and extracellular matrix (ECM) cross-linking, can be demonstrated through immunohistochemistry and digital morphometry. This review integrates molecular signaling and morphologic evidence to delineate the mechanisms of cardiac fibrosis, emphasizing the pathologist’s role as a link between molecular insight and diagnostic interpretation. Understanding these intertwined processes provides the foundation for novel antifibrotic therapies targeting key molecular nodes of fibroblast activation and matrix remodeling. Full article

Background: Arterial hypertension (AH) is a frequent comorbidity in patients with osteoarthritis (OA). Among antihypertensive agents, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), and beta-blockers (βBs) have been suggested to influence OA progression and symptomatology. The aim of this study was to assess whether the duration of effectiveness (DE) of viscosupplementation (VS) differs between patients with knee OA who are receiving antihypertensive treatment and those who are not. Methods: This post hoc analysis was conducted using data from a cross-sectional clinical trial (ClinicalTrials.gov Identifier: NCT04988698). The study included consecutive patients with knee OA who came for consultation at the Rheumatology Department and had received intra-articular hyaluronic acid injections within the past three years. The primary outcome was DE, self-reported by patients as the number of weeks of symptom relief. Associations between DE and various factors, including demographics, disease duration, radiographic OA severity (Kellgren–Lawrence grade and affected compartments), comorbidities, OA treatment history, antihypertensive therapy, physical activity level, and prior VS sessions, were analyzed using bivariate and multivariate models. Results: A total of 105 patients (65 women, 149 treated knees) were included. The mean age was 66.1 ± 13.2 years, and the mean body mass index (BMI) was 27.5 kg/m². Thirty-eight percent of patients were receiving antihypertensive treatment (mean number of agents: 1.9; range: 1–4), including CCBs (n = 15), ACE inhibitors (n = 13), ARBs (n = 7), βBs (n = 6), and diuretics (n = 2). The overall mean DE of VS was 48.2 ± 24.8 weeks, with a trend toward longer DE in hypertensive patients compared to non-hypertensive patients (53.1 ± 31.3 vs. 45.4 ± 19.8 weeks, p = 0.06). Bivariate analysis identified significantly longer DE in patients with BMI < 27.5 kg/m² (p = 0.002), Kellgren–Lawrence grade < 4 (p = 0.008), an active lifestyle (p = 0.005), unicompartmental OA (p = 0.01), medial tibiofemoral joint space narrowing (p = 0.046), and fewer than four prior VS sessions (p = 0.02). In multivariate analysis, AH was strongly associated with prolonged DE (p < 0.001), despite AH patients having a higher BMI (29.8 ± 5.5 vs. 25.2 ± 5.2 kg/m², p = 0.001) and being more frequently sedentary (25.5% vs. 13.8%, p = 0.07). A trend toward longer DE was observed in patients treated with βBs and ARBs but not with CCBs or ACE inhibitors. Additional independent predictors of longer DE included BMI < 27.5 kg/m² (p < 0.001), unicompartmental OA (p = 0.02), fewer than four prior VS sessions (p = 0.02), and an active lifestyle (p = 0.027). Conclusions: These findings suggest that antihypertensive treatment may extend the effectiveness of viscosupplementation in knee OA. However, the sample size was insufficient to determine whether specific classes of antihypertensive agents provide greater benefits. Further large-scale, prospective studies are warranted to clarify the potential impact of antihypertensive medications on viscosupplementation outcomes in knee OA. Full article

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), exploits angiotensin-converting enzyme 2 (ACE2) for cell entry, implicating the renin–angiotensin system (RAS) in disease pathogenesis. Hypertension (HT), a major comorbidity, is strongly influenced by genetic factors within RAS, including angiotensin ii receptor type 1 (AGTR1) and ACE2) polymorphisms. However, data on these variants in African populations remain scarce. This study investigated associations between AGTR1 and ACE2 single-nucleotide polymorphisms (SNPs), HT, and COVID-19 severity in patients at a Tshwane Academic Hospital. Methods: We genotyped AGTR1 and ACE2 SNPs in 94 PCR-confirmed COVID-19 patients using Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight (MALDI-TOF) mass spectrometry. Clinical data were extracted from hospital records. Ordinal logistic regression models assessed relationships between SNPs, HT, and COVID-19 severity. Results: The cohort (mean age: 53.9 years; HT prevalence: 54.9%) exhibited mild (54.9%), moderate (18.6%), and severe (26.5%) COVID-19. Although the rs2106809 A genotype appeared to be associated with lower odds of severe disease (OR = 0.39, 95% CI: 0.14–1.08, p = 0.04), this observation should be interpreted with caution given the limited sample size of this study. Other SNPs and clinical variables showed no significant associations. Conclusions: This exploratory study represents the first description of AGTR1 and ACE2 SNP patterns in COVID-19 patients from Tshwane. While the rs2106809 variant may indicate a possible protective trend, the evidence remains preliminary. Age correlated with severity. Larger, multi-ethnic studies are needed to confirm these findings. Full article

Background: Pressure overload-induced heart failure (HF) involves cardiac remodeling, ferroptosis, and impaired mitophagy. Yixinjiedu formula (YXJDF), a traditional Chinese medicine, shows cardiovascular protective effects, but its underlying mechanisms remain largely unclear. This study aims to evaluate the cardioprotective effect of YXJDF in pressure overload-induced HF and explore its regulatory role in ferroptosis and mitophagy. Methods: A transverse aortic constriction (TAC) mouse model and angiotensin II-induced HL-1 cardiomyocytes were used to assess the therapeutic effects of YXJDF. Cardiac function, ferroptosis, and mitophagy were evaluated using histological, biochemical, molecular, and imaging analyses. Autophagic flux was assessed using lysosomal inhibition. Network pharmacology was applied to identify potential targets, while LC-MS/MS profiling and molecular docking were used to characterize major constituents of YXJDF and predict target interactions. Results: In TAC mice, YXJDF significantly improved cardiac function and attenuated myocardial hypertrophy and fibrosis. YXJDF suppressed ferroptotic injury, as evidenced by reduced lipid peroxidation, restoration of GPX4 and FTH1 expression, and normalization of antioxidant capacity. Mitophagy was restored, as indicated by increased PINK1 and Parkin expression, enhanced LC3-II accumulation, and reduced p62 and TOM20 levels, and as confirmed by autophagic flux analysis. Consistent protective effects on ferroptosis and mitophagy were observed in angiotensin II-induced cardiomyocytes. Network pharmacology analysis identified PINK1 as a key target, which was validated by in vivo and in vitro experiments. LC-MS/MS identified 20 major chemical constituents in YXJDF, and molecular docking showed strong binding affinity between several compounds (e.g., calycosin, salvianolic acid A) and PINK1. Conclusions: YXJDF ameliorates pressure overload-induced cardiac injury by restoring PINK1/Parkin-mediated mitophagy and suppressing ferroptosis. These findings reveal a multi-target mechanism underlying the therapeutic potential of YXJDF in HF. Full article