Search Results (356)

Myocardial infarction (MI) is an inflammatory disease responsible for approximately 75% of sudden cardiac deaths. In this study, we aimed to evaluate the cardio-protective influence of microencapsulated probiotic and synbiotic dietary supplements in vivo and in molecular docking studies. MI was induced in rats with the injection of isoproterenol (i.p. 67 mg/kg). Plasma lipid profiles and the levels of oxidative stress markers, inflammatory markers, and cardiac enzymes were determined. The expression levels of MMP-7 and IL-1β in the heart muscle were measured. The impact of dietary supplements on fecal bacterial counts was evaluated across all rat groups. A histopathological examination of cardiac tissue was performed. The cardio-protective potential of cyanidin 3-diglucoside 5-glucoside and arabinoxylan was studied using molecular docking. The results demonstrate that all tested dietary supplements induced an improvement in all the biochemical parameters in association with an improvement in myocardial muscle tissue. The mRNA expression levels of MMP-7 and IL-1β were significantly downregulated by all dietary supplements. All dietary supplements increased the fecal counts of probiotic strains. In the molecular docking analysis, cyanidin 3-diglucoside 5-glucoside exhibited binding affinity values of −8.8 and −10 for lactate dehydrogenase (LDH) and Paraoxonase 1 (PON1), respectively. Arabinoxylan showed similar binding affinity (−8.8) for both LDH and PON1. Conclusion: Microencapsulated probiotic and synbiotic dietary supplements demonstrated notable cardio-protective influence in vivo and in molecular docking studies. These supplements may serve as promising candidates for the prevention of myocardial infarction. Full article

Cardiac remodeling in feline hypertrophic cardiomyopathy (HCM) is poorly understood. To investigate underlying molecular mechanisms, we determined microRNA–mRNA interactions, regulatory networks, and upstream regulators using left ventricle (LV) and left atrium (LA) mRNA and microRNA sequencing datasets from cats with HCM and controls. Upstream regulators, molecules, and pathways associated with ischemia, inflammation, fibrosis, and cellular changes were observed in the HCM heart. In both the HCM LV and LA, TNFα, IL1β, and TGFβ were identified as upstream regulators, along with FGF23, THBS4, and FAMB177 as the top increased molecules. Relevant microRNAs included upstream regulator miR-132, enriched miR-124-3p, miR-122b-3p, miR-146-5p (HCM LV and LA), miR-370, miR-1185-5p, miR-12194-3p (HCM LV), miR-153-3p, miR-185-5p, and miR-185-3p (HCM LA). Macrophage pathways were activated, and granulocyte and agranulocyte adhesion and diapedesis were the most connected pathways. The HIF1α signaling pathway in the HCM LV, upstream regulators miR-1-3p and miR-204, and reduced miR-29 and miR-122-5p suggest cardioprotective mechanisms. Observed in the healthy heart and suspected to be involved in cardiac homeostasis were upstream regulators miR-96, inhibited WNT3A and miR-145, as well as miR-140-5p, miR-141-3p, miR-208b-3p, and miR-885-3p. This study provides further insights into the pathogenesis of HCM, and identifies the factors involved in the maintenance of a healthy LV and LA. Full article

Background: Heart failure (HF) is associated with an increased risk of cognitive impairment and hippocampal dysfunction, yet the underlying molecular mechanisms remain poorly understood. This study aims to investigate the role of microRNA (miRNA) networks in hippocampus-dependent memory recovery in a mouse model of HF. Methods: CaMKIIδC transgenic (TG) mice, a model for HF, were used to assess hippocampal function at 3 and 6 months of age. Memory performance was evaluated using hippocampus-dependent behavioral tasks. Small RNA sequencing was performed to analyze hippocampal miRNA expression profiles across both time points. Bioinformatic analyses identified miRNAs that potentially regulate genes previously implicated in HF-induced cognitive impairment. Results: We have previously shown that at 3 months of age, CaMKIIδC TG mice exhibited significant memory deficits associated with dysregulated hippocampal gene expression. In this study, we showed that these impairments, memory impairment and hippocampal gene expression, were no longer detectable at 6 months, despite persistent cardiac dysfunction. However, small RNA sequencing revealed a dynamic shift in hippocampal miRNA expression, identifying 27 miRNAs as “compensatory miRs” that targeted 73% of the transcripts dysregulated at 3 months but reinstated by 6 months. Notably, miR-181a-5p emerged as a central regulatory hub, with its downregulation coinciding with restored memory function. Conclusions: These findings suggest that miRNA networks contribute to the restoration of hippocampal function in HF despite continued cardiac pathology and provide an important compensatory mechanism towards memory impairment. A better understanding of these compensatory miRNA mechanisms may provide novel therapeutic targets for managing HF-related cognitive dysfunction. Full article

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, driven by diverse pathophysiological mechanisms. Among its major risk factors, obesity has emerged as a lobal public health concern affecting individuals across all age groups. The rising prevalence of obesity significantly increases the risk of cardiovascular complications, including the development and progression of HF. MicroRNAs (miRNAs), small non-coding RNA molecules, have garnered attention for their regulatory roles in cardiovascular disease, particularly through post-transcriptional modulation of gene expression. This review highlights the involvement of miRNAs in key pathological processes observed in the obese heart, including cardiac remodeling, apoptosis, angiogenesis, inflammation, mitochondrial dysfunction, and myocardial lipotoxicity. Understanding how specific miRNAs and their targets contribute to HF in the context of obesity may inform the development of novel RNA-based therapeutic strategies for cardiometabolic disease. Full article

Background: Adverse cardiac remodeling drives heart failure progression, but the role of hyaluronan-binding protein (HYBID) in this process remains unclear. This study investigated the role of HYBID as a key profibrotic factor in the progression of adverse cardiac remodeling with a focus on its functional impact on cardiac fibroblasts and underlying molecular mechanisms. Methods: RNA sequencing analysis was employed to identify differentially expressed genes in mouse ventricular tissue post-myocardial infarction (MI). Fibroblast-specific genetically modified mouse models (knockdown and overexpression) were generated using FSP1 promoter-driven adeno-associated viruses. Comprehensive histological and biochemical assessments were conducted both in vivo and in vitro to evaluate the effects of HYBID modulation on cardiac remodeling. Molecular docking and immunoprecipitation assays were utilized to elucidate the mechanistic interactions between HYBID and its downstream targets. Results: RNA sequencing revealed HYBID as a fibroblast-enriched protein significantly upregulated in myocardial tissue of MI mice. Fibroblast-specific knockdown of HYBID attenuated MI-induced fibroblast activation, improved cardiac function, and mitigated adverse cardiac remodeling. Conversely, HYBID overexpression exacerbated fibroblast activation and promoted cardiac remodeling. Mechanistically, HYBID was found to competitively bind to STAT5A, thereby inhibiting the anti-fibrotic effects of MMP13 and driving fibroblast activation and adverse remodeling post-MI. Conclusions: Our findings establish HYBID as a novel fibroblast-enriched regulator that exacerbates fibrosis and adverse cardiac remodeling following MI. By uncovering the HYBID–STAT5A–MMP13 axis as a critical signaling pathway, this study provides new insights into the molecular mechanisms underlying heart failure progression. Full article

Congenital heart diseases (CHDs) are among the most common congenital malformations. Despite significant advancements in understanding the embryonic development of the heart, the etiology of CHDs remains largely unknown. The complexity of the processes involved in heart formation limits our ability to identify all molecular mechanisms underlying CHDs. Recently, microRNAs (miRNAs) have provided new insights into the molecular mechanisms of CHDs. This narrative review evaluates the evidence linking expression to CHDs and discusses the potential of RNA expression regulation as a promising avenue for therapeutic biomarker development. A search of the literature, focusing on the role of miRNAs in CHDs, was carried out to identify pertinent studies published over the last decade. The literature search was performed utilizing the PubMed and Scopus databases. The selection criteria included peer-reviewed original studies, clinical research, meta-analyses, and review articles written in English. Multiple investigations have highlighted the essential role of miRNAs in cardiac development and function, showing that their distinct expression patterns can broadly and specifically influence cellular signaling pathways involved in heart abnormalities. The regulation of mRNA expression emerges as a key factor in the pathogenesis of CHD, paving the way for the identification of novel molecular biomarkers. Alterations in transcriptional profiles could offer innovative and highly specific tools for risk stratification and the clinical monitoring of patients. In conclusion, although further studies are needed to validate the efficacy and clinical applicability of these biomarkers, the mRNA-based approach stands out as a promising perspective for precision medicine in the CHD context. Full article

Aortic dissection (AD) is a life-threatening vascular condition with limited pharmacological options, and shared risk factors with cardiac disease include hypertension, atherosclerosis, smoking, and dyslipidemia. This study investigated Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, in a BAPN/Ang-II-induced mouse model of AD, revealing significant therapeutic potential. Fer-1 significantly reduced AD incidence and mortality by preserving aortic wall integrity. RNA sequencing identified 922 differentially expressed genes, with 416 upregulated and 506 downregulated. Bioinformatics analysis revealed that Fer-1 modulates key regulators, such as MEF2C and KDM5A, impacting immune responses, oxidative stress, apoptosis, and lipid metabolism. Additionally, Fer-1 alters miRNA expression, with the upregulation of miR-361-5p and downregulation of miR-3151-5p, targeting pathways involved in inflammation, oxidative stress, and smooth muscle cell (SMC) phenotypic stability. Functional pathway analysis highlighted the inhibition of actin cytoskeleton, ILK, and IL-17 signaling, essential for SMC differentiation and extracellular matrix remodeling. Gene interaction network analysis identified 21 central molecules, including CXCR3, ACACA, and BPGM, associated with lipid metabolism, inflammation, and vascular remodeling. This research elucidates the mechanism of ferroptosis in AD pathogenesis and establishes Fer-1 as a promising therapeutic intervention. AD and cardiac diseases share molecular mechanisms, risk factors, and pathological processes, positioning AD within the broader scope of cardiovascular pathology. By attenuating lipid peroxidation, oxidative stress, and inflammation, Fer-1 may have cardioprotective effects beyond AD, providing a foundation for future translational research in cardiovascular medicine. Full article

EPCs play important roles in the maintenance of vascular repair and health. Aging is associated with both reduced numbers and functional impairment of EPCs, leading to diminished angiogenic capacity, impaired cardiac repair, and increased risk for cardiovascular disease (CVD). The molecular mechanisms that govern EPC function in cardiovascular health are not fully understood, but there is increasing evidence that microRNAs (miRNAs) play key roles in modulating EPC functionality, endothelial homeostasis, and vascular repair. We aimed to determine how aging alters endothelial progenitor (EPC) health and functionality by altering key miRNA-mRNA pathways. To identify key miRNA-mRNA pathways contributing to diminished EPC functionality associated with aging, microRNA and mRNA profiling were conducted in EPCs from young and aged C57BL/6 mice. We identified a complex aging-associated regulatory network involving two miRNAs—miR-29c-3p and -126a—that acted in tandem to impair vascular endothelial growth factor signaling through targeting Klf2 and Spred1, respectively. The modulation of components of the miR-29c-3p–Klf2–miR-126a–Spred-1–Vegf signaling pathway altered EPC self-renewal capacity, vascular tube formation, and migration in vitro, as well as cardiac repair in vivo. The miR-29c-3p–Klf2–miR-126a–Spred1–Vegf signaling axis plays a critical role in regulating the aging-associated deficits in EPC-mediated vascular repair and CVD risk. Full article

Although a myocardial infarction occurs roughly every minute in the U.S. alone, medical research has yet to unlock the key to fully enabling post-hypoxic myocardial regeneration. Thymosin beta-4 (TB4), a short, secreted peptide, was shown to possess a beneficial impact regarding myocardial cell survival, coronary re-growth and progenitor cell activation following myocardial infarction in adult mammals. It equally reduces scarring, however, the precise mechanisms through which the peptide assists this phenomenon have not been properly elucidated. Accordingly, the primary aim of our study was to identify novel molecular contributors responsible for the positive impact of TB4 during the remodeling processes of the infarcted heart. We performed miRNA profiling on adult mice hearts following permanent coronary ligation with or without systemic TB4 injection and searched for targets and novel mechanisms through which TB4 may mitigate pathological scarring in the heart. Our results revealed a significant increase in miR139-5p expression and identified ROCK1 as a potential target protein aligned. Real-time PCR, Western blot and immunostaining on adult mouse hearts and human cardiac cells revealed the peptide indirectly or directly modulates ROCK1 protein levels both in vivo and in vitro. We equally discovered TB4 may reverse or inhibit fibroblast/myofibroblast transformation and the potential downstream mechanisms by which TB4 alters cellular responses through ROCK1 are cell type specific. Given the beneficial effects of ROCK1 inhibition in various cardiac pathologies, we propose a potential utilization for TB4 as a ROCK1 inhibitor in the future. Full article

The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling. Full article

Despite significant advancements in medical and surgical care, the morbidity and mortality rates of neonates and infants undergoing congenital cardiac surgery remain high. To identify new pathomechanisms associated with postoperative organ dysfunction, extracellular vesicles (EVs) were isolated from plasma from neonates and infants with or without organ dysfunction at three different time points around congenital cardiac surgery, and the EV miRNA expression profiles in the plasma were analyzed. A clear distinction was observed between the organ dysfunction (OD) and non-organ dysfunction (NOD) groups based on their EV miRNA expression profiles. Apoptosis and proinflammatory pathways were consistently upregulated across all time points in the OD group. Complement and coagulation cascades unexpectedly displayed downregulation at the end of the surgery in the OD group, which was verified further at the proteomic level in an independent patient cohort. The neutrophil extracellular trap (NET) formation was enhanced in the OD group across all time points compared to that in the NOD group. As NETs are known to consume complement components, these observed events might be interconnected. A feature selection machine learning method identified miR-200b-5p, miR-4800-5p, miR-363-3p, and miR-483-5p as robustly linked to organ dysfunction following congenital cardiac surgery (accuracy score = 9; SD in accuracy = 0.3162). In conclusion, our study suggested that neonates and infants with postoperative organ dysfunction were associated with enhanced NET formation and complement consumption. Full article

The present study provides a detailed review of cardiovascular biomarkers critical for the diagnosis, prognosis, and pathophysiology of cardiovascular diseases, the leading cause of global morbidity and mortality. These biomarkers aid in detecting disease onset, progression, and therapeutic responses, providing insights into molecular mechanisms. Enzyme markers like AST, CK-MB, LDH, CA-III, and HBDH are pivotal for detecting myocardial injury during acute events. Protein markers such as CRP, H-FABP, and MPO shed light on inflammation and oxidative stress. Cardiac Troponins, the gold standard for myocardial infarction diagnosis, exhibit high specificity and sensitivity, while IMA and GPBB indicate ischemia and early myocardial damage. Peptide markers, including BNP and NT-proBNP, are crucial for heart failure diagnosis and management, reflecting ventricular stress and remodeling. Novel peptides like MR-proANP and MR-proADM aid in assessing disease severity. Lipid markers such as lipoprotein-associated phospholipase A2 and oxylipins provide insights into lipid metabolism and atherosclerosis. Inflammatory and stress-related biomarkers, including TNFα, IL-6, GDF-15, and Pentraxin 3, illuminate chronic inflammation in CVDs. Hormonal markers like copeptin and endothelin-1 highlight neurohormonal activation, while emerging markers such as ST2, galectin-3, PAPP-A, and TMAO elucidate fibrosis, remodeling, and metabolic dysregulation. The inclusion of microRNAs and long non-coding RNAs represents a breakthrough in biomarker research, offering sensitive tools for early detection, risk stratification, and therapeutic targeting. This review emphasizes the diagnostic and prognostic utility of these biomarkers, advancing cardiovascular care through personalized medicine. Full article

Cardiovascular disease (CVD) remains the leading cause of death globally, with myocardial infarction (MI) being a major contributor. The current therapeutic approaches are limited in effectively regenerating damaged cardiac tissue. Up-to-date strategies for heart regeneration/reconstitution aim at cardiac remodeling through repairing the damaged tissue with an external cell source or by stimulating the existing cells to proliferate and repopulate the compromised area. Cell reprogramming is addressed to this challenge as a promising solution, converting fibroblasts and other cell types into functional cardiomyocytes, either by reverting cells to a pluripotent state or by directly switching cell lineage. Several strategies such as gene editing and the application of miRNA and small molecules have been explored for their potential to enhance cardiac regeneration. Those strategies take advantage of cell plasticity by introducing reprogramming factors that regress cell maturity in vitro, allowing for their later differentiation and thus endorsing cell transplantation, or promote in situ cell proliferation, leveraged by scaffolds embedded with pro-regenerative factors promoting efficient heart restoration. Despite notable advancements, important challenges persist, including low reprogramming efficiency, cell maturation limitations, and safety concerns in clinical applications. Nonetheless, integrating these innovative approaches offers a promising alternative for restoring cardiac function and reducing the dependency on full heart transplants. Full article

Using an atrial fibrillation (AF) model in spontaneously hypertensive rats (SHRs), we aimed to identify circulating miRNAs for AF diagnosis and prediction and to confirm the cardiac origin of these miRNAs. A total of 31 SHRs and 39 Wistar Kyoto (WKY) normotensive controls were randomized into six groups: young, adult, and aging SHR and WKY. Spontaneous AF burden and atrial and circulating levels of 11 miRNAs were quantified. Spontaneous AF was absent in all WKY rats. In the SHRs, AF episodes were observed in two adult animals and in all aging animals (13.6 ± 2.3 episodes/24 h). The atrial levels of five miRNAs were significantly higher in adult and aging SHRs compared to their WKY controls (all p < 0.05). Of these, only the circulating levels of miR-328 were significantly higher in the aging SHRs vs. WKYs (p < 0.0001). Atrial miR-328 levels in the SHRs increased progressively with age (p < 0.001) and correlated with circulating miR-328 levels (r = 0.58; p < 0.01). Among aging SHRs, atrial levels of miR-328 strongly correlated with AF burden (r = 0.79; p < 0.01). These data suggest that the circulating level of miR-328 could emerge as a promising marker for both AF diagnosis and, if assessed dynamically, for AF prediction. Full article

Inhibition of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) causes the stabilization of hypoxia-inducible factor-1α and -2α (HIF-1α and HIF-2α) to regulate various cell signaling pathways. Hypoxia-inducible factor (HIF) is crucial in regulating signal responses mediated by hypoxia. HIF regulates the transcription of many genes involved in the response to hypoxia and ischemic insult. Our current work investigates the protective effects of PHD1 knockout in mice against myocardial infarction. Study Design: Myocardial infarction (MI) was induced by left anterior descending coronary artery (LAD) ligation (8–12-week-old mice) in both wild-type (WT) and PHD1 knockout (PHD1^−/−) mice. WT sham (S) and PHD1^−/−S group mice underwent surgery without LAD ligation. Thirty days post-surgery, cardiac functions were measured by echocardiogram. Mice in all the groups were euthanized at various time points for tissue collection post-MI 8 h (gel shift and microarray analysis), 4 days (Western blot analysis), 7 days (blood vessel density), or 30 days (histological analysis). For microarray analysis, WTMI and PHD1^−/−MI group mices’ heart tissue was used for RNA isolation, then hybridization to a GeneChip™ Mouse Gene 1.0 ST Array as per the manufacturer’s instructions. Bioinformatic analysis was performed using the transcriptome analysis console (TAC) to generate a list of differentially regulated genes, followed by ingenuity pathway analysis. Results: The study findings revealed a significant increase in vessel density (capillary and arteriolar density) in the PHD1^−/−MI mice compared to those with WTMI. The echocardiographic examination demonstrated that the PHD1^−/−MI mice group had an increased ejection fraction and fractional shortening than the WT mice 30 days post-MI. HIF-1α DNA binding activity was higher in PHD1^−/−MI mice than in WTMI. The Western blot analysis showed a significant increase in the expression of HSPA12B in the PHD1^−/−MI compared to WTMI mice. Bioinformatic analysis using TAC software, Version 4.0.2.15 (1.5 fold, p < 0.05) showed 174 differentially regulated genes. Conclusions: In conclusion, our study showed PHD1 knockout activates several important molecules and signaling pathways, resulting in increased angiogenesis and cardioprotection against myocardial infarction. Full article