Search Results (379)

Background: Cardiomyocyte death is a key factor in myocardial ischemia–reperfusion injury (MI/RI), and the expression patterns and molecular mechanisms of pyroptosis-related genes (PRGs) in ischemia–reperfusion injury are poorly understood. Methods: The mouse MI/RI injury-related datasets GSE61592 and GSE160516 were obtained from the Gene Expression Omnibus database, and differential expression analysis was performed on each to identify differentially expressed genes (DEGs). The DEGs were intersected with the PRGs obtained from GeneCards to identify differentially expressed PRGs in MI/RI. Enrichment analysis identified key pathways, while PPI network analysis revealed hub genes. The expression patterns and immune cell infiltration of hub genes were also investigated. The molecular docking prediction of key genes was performed using MOE software in conjunction with the ZINC small molecular compounds database. Key gene expression was validated in an external dataset (GSE4105), a mouse MI/RI model, and an HL-1 cell hypoxia/reoxygenation model via RT-qPCR. Results: A total of 29 differentially expressed PRGs were identified, which are primarily associated with pathways such as “immune system process”, “response to stress”, “identical protein binding”, and “extracellular region”. Seven key genes (Fkbp10, Apoe, Col1a2, Ppic, Tlr2, Fstl1, Serpinh1) were screened, all strongly correlated with immune infiltration. Seven FDA-approved small molecule compounds exhibiting the highest docking potential with each key gene were selected based on a comprehensive evaluation of S-scores and hydrogen bond binding energies. Apoe, Tlr2, and Serpinh1 were successfully validated across external datasets, the mouse MI/RI model, and the cardiomyocyte H/R model. Conclusions: Apoe, Tlr2, and Serpinh1 may be key genes involved in MI/RI-related pyroptosis. Targeting these genes may provide new insights into the treatment of MI/RI. Full article

Mitochondrial reverse electron transport (RET) represents a fundamental but potentially hazardous metabolic process in eukaryotic cells. This review systematically examines current understanding of RET mechanisms and their pathophysiological consequences. RET occurs when electrons flow inversely from reduced coenzyme Q (CoQH₂) to complex I, driven by excessive reduction of the CoQ pool and elevated mitochondrial membrane potential, resulting in substantial superoxide production. While moderate RET contributes to physiological redox signaling, sustained RET activation leads to oxidative damage and activates regulated cell death pathways. Notably, RET demonstrates metabolic duality: it facilitates ATP generation through NAD⁺ reduction while simultaneously inducing mitochondrial dysfunction via reactive oxygen species overproduction. Pathologically, RET has been implicated in myocardial ischemia–reperfusion injury, neurodegenerative disorders including Alzheimer’s diseases, and exhibits context-dependent roles in tumor progression. Emerging evidence also suggests RET involvement in microbial pathogenesis through modulation of host immune responses. These findings position RET as a critical regulatory node in cellular metabolism with broad implications for human diseases. Future investigations should focus on developing tissue-specific RET modulators and elucidating the molecular switches governing its activation threshold, which may yield novel therapeutic strategies for diverse pathological conditions. Full article

Previous work has shown that mouse models fed a non-obesogenic high-fat diet have preserved cardiac function and no obesity-associated comorbidities such as diabetes. However, they do suffer increased cardiac vulnerability to ischemic reperfusion (I/R) injury, which has been attributed to changes in Ca²⁺ handling, oxidative stress, and mitochondrial transition pore activity. However, there have been no studies investigating the involvement of metabolites. Wild-type mice were fed either a control or a non-obesogenic high-fat diet for ~26 weeks. Key cardiac metabolites were extracted from freshly excised hearts and from hearts exposed to 30 min global ischemia followed by 45 min reperfusion. The extracted metabolites were measured using commercially available kits and HPLC. Hemodynamic cardiac function was monitored in Langendorff perfused hearts. Levels of energy-rich phosphates and related metabolites were similar for both hearts fed a control or a high-fat diet. However, the high-fat diet decreased cardiac glycogen and increased cardiac lactate, hypoxanthine, alanine, and taurine levels. Langendorff perfused hearts from the high-fat diet group suffered more ischemic stress during ischemia, as shown by the significantly shorter time needed for onset and for reaching maximal ischemic (rigor) contracture. Following I/R, there was a significant decrease in myocardial adenine nucleotides and a significant increase in the levels of alanine and purines for both groups. Most of the principal amino acids tended to fall during I/R. Hearts from mice fed a high-fat diet showed more changes during I/R in markers of energetics (phosphorylation potential and energy charge), metabolic stress (lactate), and osmotic stress (taurine). This study suggests that cardiac metabolic changes due to high-fat diet feeding, independent of obesity-related comorbidities, are responsible for the marked metabolic changes and the increased vulnerability to I/R. Full article

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia–reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC. Full article

Taxifolin is a natural flavonoid found in a variety of plants, including Siberian larch (Larix sibirica) and milk thistle (Silybum marianum), that has attracted attention for its multifaceted pharmacological properties, including cardioprotective effects. Through its antioxidant and anti-inflammatory activities, taxifolin has shown significant therapeutic potential in cardiovascular diseases such as atherosclerosis, myocardial ischemia, and diabetic cardiomyopathy. This review highlights the cardioprotective effects of taxifolin in preclinical models of atherosclerosis, ischemia/reperfusion injury, and diabetic cardiomyopathy. Taxifolin contributes to its cardioprotective effects through key mechanisms such as modulation of pathways such as PI3K/AKT and JAK2/STAT3, inhibition of NADPH oxidase, and modulation of nitric oxide production. Recent studies have shown that taxifolin can affect glucose metabolism by modulating sodium–glucose transporter (SGLT) expression, potentially enhancing the cardioprotective effects of SGLT2 inhibitors. Given the emerging role of SGLT2 inhibitors in the management of cardiovascular disease, further investigation of the interaction of this pathway with taxifolin may provide new therapeutic insights. Although taxifolin has multifaceted potential in the prevention and treatment of cardiovascular disease, further studies are needed to better understand its mechanisms and validate its efficacy in different disease stages. This review aims to provide a rationale for the clinical application of taxifolin-based cardiovascular therapies and suggest directions for future research. Full article

Background: Excessive formation of neutrophil extracellular traps (NETs) leads to NETosis, accompanied by the release of citrullinated histone H3 (CitH3), a key mediator of septic inflammation. However, the role of CitH3 in sterile inflammation, such as acute myocardial infarction (MI) and post-MI heart failure, remains incompletely understood. Methods and Results: We investigated the role of CitH3, a byproduct of NETosis, in myocardial ischemia/reperfusion (I/R) injury using a murine MI model. C57BL/6J mice were subjected to left coronary artery (LCA) occlusion followed by reperfusion and treated with either a humanized anti-CitH3 monoclonal antibody (hCitH3-mAb) or control human IgG. In mice undergoing 40 min of LCA occlusion and 24 h of reperfusion, hCitH3-mAb administered 10 min before reperfusion significantly reduced infarct size by 36% compared to control (p < 0.05). Plasma levels of CitH3, IL-1β, and interferon-β were significantly elevated following MI but were attenuated by hCitH3-mAb. In addition, plasma and cardiac tissue from treated mice showed significantly lower levels of citrate synthase, a marker of mitochondrial injury, suggesting that hCitH3-mAb preserved mitochondrial integrity after MI. In mice undergoing 50 min of LCA occlusion and 21 days of reperfusion, longitudinal echocardiography revealed preservation of left ventricular ejection fraction (LVEF) in hCitH3-mAb-treated mice, with significant improvement observed on days 7, 14, and 21 post-MI (p < 0.05 vs. control). hCitH3-mAb also mitigated myocardial fibrosis and preserved tissue architecture. Conclusions: These findings demonstrated CitH3 as a critical mediator of myocardial injury and adverse remodeling following acute MI. Neutralization of CitH3 via hCitH3-mAb attenuates I/R injury and preserves cardiac function by mitigating inflammation and protecting mitochondrial integrity. Targeting CitH3 represents a promising therapeutic strategy to prevent heart failure following MI. Full article

Background/Objectives: Naringin, a major flavonoid found in citrus fruits, has garnered significant attention over the past two decades for its potential cardiovascular benefits. This systematic review evaluates the effects of naringin on endothelial function and myocardial performance, with particular emphasis on ischemia-reperfusion (I/R) injury, based on the literature published from January 2000 to June 2025. Methods: The review was conducted in accordance with PRISMA 2020 guidelines. A comprehensive search of PubMed, Scopus, EMBASE, and Web of Science databases was performed using key terms including “naringin”, “cardiovascular”, “endothelial function”, “atherosclerosis”, and “ischemia-reperfusion.” A total of 62 studies were included and categorized into three domains: cellular models, animal studies, and human trials. Risk of bias assessments were conducted for each study type using appropriate tools. Results: Naringin consistently exhibited antioxidant, anti-inflammatory, and vasoprotective effects across all study types. Mechanistic studies highlighted the modulation of key signaling pathways, including PI3K/Akt, NF-κB, Nrf2, the renin-angiotensin system (RAS), and enhancement of KATP channel expression, as well as its ability to inhibit apoptosis, autophagy, and ferroptosis. In animal models, naringin improved endothelium-dependent vasorelaxation, reduced infarct size, and preserved myocardial function. Although limited, human trials reported beneficial effects on lipid profiles, arterial stiffness, and adiponectin levels. Conclusions: Naringin demonstrates strong potential as a dietary adjunct for cardiovascular protection, especially in the context of ischemic injury and vascular dysfunction. Further well-designed clinical trials are needed to define optimal dosing strategies and improve its bioavailability in humans. Full article

Cardiovascular diseases (CVD), such as myocardial hypertrophy, heart failure, atherosclerosis, and myocardial ischemia/reperfusion (I/R) injury, are among the major threats to human health worldwide. Post-translational modifications alter the function of proteins through dynamic chemical modification after synthesis. This mechanism not only plays an important role in maintaining homeostasis and plays a crucial role in maintaining normal cardiovascular function, but is also closely related to the pathological state of various diseases. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression, and play important roles in post-translational modification by catalyzing the deacetylation of key lysine residues in nucleosomal histones, which are closely associated with the occurrence and development of cardiovascular diseases. Recent studies indicate that HDAC inhibitors (HDACis) may represent a new class of drugs for the treatment of cardiovascular diseases by influencing post-translational modifications. In this review, we systematically summarize the mechanism of action of HDACs and HDACis in post-translational modifications related to common cardiovascular diseases, providing new ideas for the treatment of CVD, and explore possible future research directions on the relationship between HDAC and HDACi in post-translational modifications and cardiovascular diseases. Full article

Over the past four decades, cardioprotective research has revealed an extraordinary complexity of cellular and molecular mechanisms capable of mitigating ischemia/reperfusion injury (IRI). Among these, ischemic conditioning has emerged as one of the most influential discoveries: brief episodes of ischemia followed by reperfusion activate protective programs that reduce myocardial damage. These effects can be elicited locally (pre- or postconditioning) or remotely (remote conditioning), acting mainly through paracrine signaling and mitochondria-linked kinase pathways, with both early and delayed windows of protection. We have contributed to clarifying the roles of mitochondria, oxidative stress, prosurvival kinases, connexins, extracellular vesicles, and sterile inflammation, particularly via activation of the NLRP3 inflammasome. Despite robust preclinical evidence, clinical translation of these approaches has remained disappointing. The challenges largely stem from experimental models that poorly reflect real-world clinical settings—such as advanced age, comorbidities, and multidrug therapy—as well as the reliance on surrogate endpoints that do not reliably predict clinical outcomes. Nevertheless, interest in multi-target protective strategies remains strong. New lines of investigation are focusing on emerging mediators—such as gasotransmitters, extracellular vesicles, and endogenous peptides—as well as targeted modulation of inflammatory responses. Future perspectives point toward personalized cardioprotection tailored to patient metabolic and immune profiles, with special attention to high-risk populations in whom IRI continues to represent a major clinical challenge. Full article

Objective: This study aimed to investigate the cardioprotective effects of bosentan, an endothelin receptor antagonist, in a rat model of lung ischemia–reperfusion (I/R) injury, with a focus on myocardial tissue involvement. Methods: Twenty-four male Wistar rats were randomly assigned to four groups: sham, bosentan, I/R, and I/R + bosentan. Lung I/R injury was induced by hilar clamping for 45 min, followed by 60 min of reperfusion. Bosentan (30 mg/kg) was administered intraperitoneally 30 min prior to the procedure. Myocardial tissue was evaluated histopathologically for structural disorganization, inflammation, fibrosis, and edema. TGF-β1 protein levels in myocardial tissue were compared across the groups using β-actin as the loading control. ELISA was used to quantify ET-1, NF-κB, and p53 levels, while spectrophotometric analysis was employed to assess MDA levels and the activities of SOD and CAT enzymes in heart tissue. Results: The I/R group exhibited significant myocardial disorganization, inflammation, and interstitial edema compared to the sham and bosentan groups. Bosentan treatment markedly ameliorated these histopathological alterations. Additionally, the I/R group showed elevated levels of ET-1, NF-κB, p53, and MDA, along with reduced SOD and CAT activities; these changes were significantly attenuated by bosentan administration. Bosentan treatment significantly reduced myocardial ET-1 levels (from 136.88 ± 5.02 to 120.18 ± 2.67 nmol/g, p = 0.003), NF-κB levels (from 0.87 ± 0.04 to 0.51 ± 0.03 ng/mg, p = 0.002), and TGF-β1 expression (from 1.72 ± 0.10 to 0.91 ± 0.08 relative units, p = 0.001). Moreover, bosentan increased antioxidant enzyme activities, elevating SOD levels from 21.45 ± 1.23 to 32.67 ± 1.45 U/mg protein (p = 0.001) and CAT levels from 15.22 ± 0.98 to 25.36 ± 1.12 U/mg protein (p = 0.002). Conclusions: Bosentan exerts cardioprotective effects in rats subjected to lung I/R injury by reducing myocardial damage, inflammation, and oxidative stress. These findings suggest that bosentan may serve as a potential therapeutic agent for preventing remote organ injury associated with pulmonary I/R. Full article

Coronary microvascular obstruction and dysfunction (CMVO) frequently arise following primary percutaneous coronary intervention (PCI), particularly in individuals with myocardial infarction. Despite the restoration of epicardial blood flow, microvascular perfusion might still be compromised, resulting in negative clinical outcomes. CMVO is a complex condition resulting from a combination of ischemia, distal thrombotic embolization, reperfusion injury, and individual susceptibilities such as inflammation and endothelial dysfunction. The pathophysiological features of this condition include microvascular spasm, endothelial swelling, capillary plugging by leukocytes and platelets, and oxidative stress. Traditional angiographic assessments, such as Thrombolysis in Myocardial Infarction (TIMI) flow grade and myocardial blush grade, have limited sensitivity. Cardiac magnetic resonance imaging (CMR) stands as the gold standard for identifying CMVO, while the index of microvascular resistance (IMR) is a promising invasive option. Treatment approaches involve powerful antiplatelet drugs, anticoagulants, and supersaturated oxygen, yet no treatment has been definitively shown to reverse established CMVO. CMVO remains a significant therapeutic challenge in coronary artery disease management. Enhancing the comprehension of its core mechanisms is vital for the development of more effective and personalized treatment strategies. Full article

Coronary no-reflow (CNR) is the failure of blood to reperfuse ischemic myocardial tissue after restoration of the vasculature. CNR poses a significant clinical challenge in the treatment of patients with ST-segment elevation myocardial infarction (STEMI), as it increases mortality and the risk of major adverse cardiac events (MACEs). Myocardial ischemia with subsequent reperfusion results in severe damage to the cardiac microcirculation. The pathophysiological causes of CNR include cardiomyocyte vulnerability, capillary and endothelial damage, leukocyte activation, reactive oxygen species (ROS) production, and changes in microRNA profiles and related gene expression. The impact of percutaneous coronary intervention (PCI) on the occurrence of CNR cannot be overlooked, as it can provoke distal atherothrombotic embolization. Current standards of pharmacological therapy for CNR are confined to intracoronary vasodilators and antiplatelet agents. As our understanding of the pathogenesis of the CNR phenomenon improves, opportunities emerge for developing novel therapeutic strategies. The following literature review provides an overview of the pathophysiology of the no-reflow phenomenon (based on animal and preclinical studies), contemporary treatment trends, and current therapeutic approaches. Full article

Background/Objectives: Ischemic postconditioning (IP) is a well-established intervention that mitigates this damage by activating endogenous cardioprotective pathways. However, the presence of comorbidities such as dyslipidemia can disrupt these protective mechanisms and abolish the infarct-sparing effect typically induced by IP. In this context, identifying pharmacological strategies to restore cardioprotection is of clinical relevance. This study aimed to evaluate whether N-acetylcysteine (NAC), a glutathione precursor with antioxidant properties, can restore the infarct-limiting effect of IP compromised by HFD-induced oxidative stress. Methods: Male mice were fed a control diet (CD) or HFD for 12 weeks. NAC (10 mM) was administered in drinking water for 3 weeks before ex vivo myocardial ischemia/reperfusion (I/R) injury (30 min ischemia/60 min reperfusion). In IP groups, six cycles of brief I/R were applied at the onset of reperfusion. Infarct size, ventricular function, redox status (GSH/GSSG), lipid profile, and histology were evaluated. Results: NAC improved the lipid profile (HDL/non-HDL ratio) and enhanced the infarct-sparing effect of IP in CD-fed mice. In HFD-fed mice, NAC restored the efficacy of IP, significantly reducing infarct size (HFD-I/R-NAC: 39.7 ± 4.5% vs. HFD-IP-NAC: 26.4 ± 2.0%, p < 0.05) without changes in ventricular function. The ratio of oxidized/reduced glutathione (GSSG/GSH) is depicted. Under basal conditions, the hearts of mice fed an HFD exhibited a shift towards a more oxidized state compared to the control diet CD group. In the I/R protocol, a significant shift towards a more oxidized state was observed in both CD and HFD-fed animals. In the IP protocol, the GSSG/GSH ratio revealed a tendency to basal values in comparison to the I/R protocol. The analysis indicates that animals subjected to I/R and IP protocols in conjunction with NAC show a tendency to reach basal values, thus suggesting a potential for the reduction in ROS. Conclusions: NAC treatment mitigates oxidative stress and restores the cardioprotective effect of ischemic postconditioning in a model of early-stage atherosclerosis. These findings support NAC as a potential adjunct therapy to improve myocardial resistance to reperfusion injury under dyslipidemic conditions Full article

Allium chinense G. Don is valued for its edible and medicinal qualities. It has been reported that Allium chinense has the potential to inhibit platelet activation, but its mechanism of action is unknown, which needs to be further explored. This study investigates the anti-myocardial ischemia–reperfusion (I/R) injury potential of Allium chinense from the perspective of platelet activation, focusing on its chemical composition and underlying mechanisms of action. A combination of transcriptome sequencing, molecular docking, and experimental validation was employed in our study. The antiplatelet active fraction MT-95ET of Allium chinense was screened by the ADP-induced platelet aggregation model in vitro. In vivo experiments demonstrated that MT-95ET can reduce the myocardial injury of I/R rats and inhibit I/R-induced platelet activation, adhesion, and aggregation. UHPLC-Q-Orbitrap-MS/MS was used to identify 13 compounds from MT-95ET. Transcriptome sequencing and molecular docking identified aerobic glycolysis key checkpoints PDK1 and PKM2 as key targets, with Sarsasapogenin and Hecogenin exhibiting strong binding affinities to these proteins. Western blot analysis further validated that MT-95ET downregulated PKM2 and PDK1, indicating a possible mechanism for its antiplatelet effects and anti-myocardial I/R injury. Full article

Poloxamer (P) 188 attenuates myocardial ischemia/reperfusion injury through cell membrane stabilization. Cell–cell interactions between endothelial cells (ECs) and cardiomyocytes (CMs) further protect CMs: co-cultures showed that, at an optimal density, ECs protected CMs against hypoxia/reoxygenation (HR) injury. The mechanism of interaction with P188 still requires exploration. We examined if N(ω)-nitro-L-arginine methyl ester (LNAME), a non-specific nitric oxide (NO) synthase inhibitor, abolishes protection in the presence or absence of P188 and/or ECs. We co-cultured mouse coronary artery ECs in an insert atop mouse CMs plated at confluency on the bottom of a well. Normoxic controls remained in complete media while HR groups were exposed to 24 h hypoxia at 0.01% O₂ in serum- and glucose-free media, followed by 2 h reoxygenation in complete media. P188 (300 μM), LNAME (40 mM), or vehicle were administered upon reoxygenation. ECs at the used lower density did not decrease HR-triggered lactate dehydrogenase release or calcium overload in CMs by themselves. P188 reduced both indicators after HR by 16/18% without and by 22/25% with ECs, respectively. LNAME abrogated CM protection by P188. Neither intervention had an effect under normoxia. Our co-culture data indicates that P188 requires NO, not necessarily of endothelial origin, to elicit CM protection. Full article