Protección miocárdica

Nephrology (Carlton). 2025 Sep;30(9):e70122. doi: 10.1111/nep.70122.

ABSTRACT

AIM: Contrast-associated acute kidney injury (CA-AKI) has higher mortality in coronary artery disease (CAD) with chronic kidney disease (CKD), undergoing coronary angiography ± revascularisation (CAG ± R). We conducted a clinical superiority trial with dichotomous outcomes to evaluate the impact of renal hypoxia mitigation with oxygen therapy (OT) on CA-AKI incidence.

METHODS: CKD stages 3-5 patients undergoing CAG ± R were assigned to the OT group (OTG) and the control therapy group (CTG). CTG received hydration only, whereas OTG received 2 L/min of pure oxygen in addition to hydration. The primary endpoint was the incidence of CA-AKI at 48 h. Secondary endpoints included patient and renal survival (doubling of serum creatinine or dialysis dependency) at 30 days, as well as intervention complications.

RESULTS: Of the 395 patients, 321 patients qualified for the per-protocol analysis (OTG: 160 and CTG: 161). CA-AKI incidence was 5.6%, and OTG observed an effective prevention (1.25% vs. 9.93%, CTG, p = 0.004). Renal and patient survival at 30 days was 100%. Three CTG patients required dialysis and were dialysis-independent at 30 days. The risk of CA-AKI incidence was high among ages > 65 years (p = 0.007), previous acute myocardial infarction (p = 0.02), CKD stage-3 (p = 0.01) and avoidance of OT use (p = 0.02). OTG had a favourable serum creatinine trend (p = 0.05). Absolute risk reduction of CA-AKI with OT was 8.7%, and the number needed to treat was 12. Interventional complications were zero.

CONCLUSION: Oxygen supplementation and saline hydration effectively prevented CA-AKI in CKD stages 3-5 patients undergoing elective CAG ± R. Hence, oxygen therapy should be a standard CA-AKI protective strategy during CAG ± R and radiocontrast-related procedures.

PMID:40984804 | DOI:10.1111/nep.70122

Eur J Prev Cardiol. 2025 Sep 22:zwaf602. doi: 10.1093/eurjpc/zwaf602. Online ahead of print.

ABSTRACT

AIMS: We studied the efficacy and safety of icosapent ethyl (IPE) 4g daily in reducing the risk of myocardial infarction (MI) across different MI subtypes and sizes, among REDUCE-IT high-risk patients with hypertriglyceridemia.

METHODS: REDUCE-IT was a phase 3b, double-blind multicenter trial. Patients with established CVD or diabetes who were treated with statins and had moderate hypertriglyceridemia were randomized to receive IPE 4g daily or placebo. The current analysis focused on MI subtypes (fatal MI, nonfatal MI, ST-segment elevation MI (STEMI), non-STEMI (NSTEMI)), as well as MI size (measured by multiples of troponin upper limit of normal) and MI-related complications. Safety outcomes included treatment emergent adverse events (TEAEs), bleeding, atrial fibrillation, and flutter.

RESULTS: At 5.7 years follow-up, MI incidence was lower with IPE compared with placebo (8.6% vs 12.0%), hazard ratio (HR) 0.69 (95% CI 0.58-0.81, P<0.0001). STEMI incidence was lower with IPE (2.7% vs 3.9%, HR 0.60, 95% CI 0.44-0.81, P=0.0008), as was NSTEMI incidence (5.9% vs 7.8%, HR 0.73, 95% CI 0.60-0.89, P=0.001). Fatal and nonfatal MIs were reduced with IPE (HR 0.55, 95% CI 0.30-1.01, P=0.05 and HR 0.70, 95% CI 0.59-0.82, P<0.0001, respectively). Stratification by size revealed IPE reduced most MIs, but the protective effect was higher for larger MIs (P<0.0001). Further analyses showed benefits in MI-related outcomes, including reductions in spontaneous MI and MI-related complications. Among patients who developed MI, safety outcomes showed no significant increase in serious bleeding, atrial fibrillation or flutter, or adverse events with IPE.

CONCLUSION: IPE significantly reduced MI across most subtypes and sizes in statin-treated patients with elevated triglycerides at increased cardiovascular risk.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01492361.

PMID:40982548 | DOI:10.1093/eurjpc/zwaf602

Arch Rehabil Res Clin Transl. 2025 Jun 3;7(3):100476. doi: 10.1016/j.arrct.2025.100476. eCollection 2025 Sep.

NO ABSTRACT

PMID:40980524 | PMC:PMC12447187 | DOI:10.1016/j.arrct.2025.100476

Drug Des Devel Ther. 2025 Sep 15;19:8339-8373. doi: 10.2147/DDDT.S547848. eCollection 2025.

ABSTRACT

This review systematically elucidates the molecular mechanisms and therapeutic potential of nuclear factor erythroid 2-related factor (Nrf) family members in the cardiovascular system. As critical components of the CNC-bZIP transcription factor family, the Nrf family (including Nrf-2/NFE2L2, Nrf-1/NFE2L1, and Nrf-3/NFE2L3) orchestrates antioxidant response element (ARE)-dependent gene expression networks, playing pivotal roles in maintaining redox homeostasis, modulating inflammatory responses, improving mitochondrial function, and regulating programmed cell death (apoptosis, autophagy, and pyroptosis). Clinical data have demonstrated that in patients with myocardial infarction, the expression of Nrf-3 gene is significantly upregulated in myocardial cells within the infarcted area. Its high expression is associated with increased in-hospital mortality during the acute phase and accelerated progression of ventricular remodeling. Knockout of the Nrf-3 gene can reduce the acute-phase mortality of myocardial infarction, improve ventricular remodeling, and enhance cardiac function. Additionally, a crossover trial involving 19 participants showed that after 2 months of administration of olive oil by-product pâté tablets, the plasma Nrf-2 level in the subjects increased by 88.9% with concurrent improvement in cardiovascular risk factors. Collectively, these findings confirm the impact of the Nrf family on cardiovascular prognosis and its potential for intervention. Furthermore, we comprehensively analyze the regulatory functions of Nrf members in major cardiovascular pathologies, including myocardial ischemia-reperfusion injury, atherosclerotic plaque formation/stabilization, and heart failure progression. Based on recent advances, we also discuss innovative therapeutic strategies targeting the Nrf pathway, encompassing pharmacological activators, gene/epigenetic therapies, combinatorial approaches, and lifestyle interventions, thereby providing a theoretical framework and novel perspectives for the precision medicine of cardiovascular diseases.

PMID:40980421 | PMC:PMC12448090 | DOI:10.2147/DDDT.S547848

World J Diabetes. 2025 Sep 15;16(9):109553. doi: 10.4239/wjd.v16.i9.109553.

ABSTRACT

BACKGROUND: Diabetic cardiomyopathy (DCM) is the leading cause of cardiovascular disease-related mortality. Farrerol (FA) possesses anti-inflammatory and antioxidant properties. However, its role in regulating endothelial ferroptosis in DCM remains unknown.

AIM: To investigate the beneficial effects of FA on cardiac microvascular dysfunction in DCM from the perspective of ferroptosis in endothelial cells (ECs).

METHODS: The mice were fed a high-fat diet and injected with streptozotocin to induce DCM. DCM mice were orally administered FA (10 and 40 mg/kg/day) and a tail vein injection of the miR-29b-3p mimic or inhibitor for 24 weeks. Cardiac function and myocardial fibrosis were also analyzed. Cardiac microvascular function was assessed using immunofluorescence and transmission electron microscopy. Ferroptosis was analyzed using RNA sequencing, immunofluorescence, and western blotting.

RESULTS: FA administration improved cardiac function, alleviated myocardial fibrosis, strengthened endothelial barrier function, suppressed endothelial inflammation, and preserved the microvascular structure in DCM mice. This improvement was associated with the inhibition of endothelial ferroptosis and downregulation of miR-29b-3p in ECs. Similar efficacy was observed after tail vein injection of the miR-29b-3p inhibitor. Inhibition of miR-29b-3p in vivo showed an anti-cardiac fibrotic effect by improving microvascular dysfunction and ferroptosis in ECs, whereas overexpression of miR-29b-3p showed the opposite effects in DCM mice. Luciferase reporter assay revealed that miR-29b-3p binds to SIRT1. In cultured ECs, FA reduced high glucose and free fatty acid (HG/FFA)-induced lipid peroxidation and ferroptosis and inhibited endothelial-mediated inflammation. However, the overexpression of miR-29b-3p partially abolished the protective effects of FA against HG/FFA-induced injury in ECs. This finding suggests that the mechanism of action of FA in improving DCM is related to the downregulation of miR-29b-3p and activation of SIRT1 expression.

CONCLUSION: Therefore, FA has a potential therapeutic effect on cardiac microvascular dysfunction by suppressing EC ferroptosis through the miR-29b-3p/SIRT1 axis.

PMID:40980297 | PMC:PMC12444265 | DOI:10.4239/wjd.v16.i9.109553

Front Chem. 2025 Sep 5;13:1643663. doi: 10.3389/fchem.2025.1643663. eCollection 2025.

ABSTRACT

INTRODUCTION: As an important gas signaling molecule, hydrogen sulfide (H2S) exhibits therapeutic potential in inflammatory and oxidative stress-related diseases. This study developed and evaluated novel H2S donor derivatives based on the phenylphosphonothioic dichloride scaffold.

METHODS: Derivatives were synthesized based on the phenylphosphonothioic dichloride scaffold. Compound 3b-1 was selected for its high H2S release capacity and favorable safety profile. Its anti-inflammatory activity was evaluated by measuring inhibition of TNF-α, TNF-β, and nitrite. Hepatoprotective effects were assessed in an H2O2-induced injury model using oxidative stress markers (MDA, SOD, GSH) and HSC activation. Cardioprotective effects were examined in an LPS-induced model by analyzing mitochondrial membrane potential, cardiac markers (LDH, CK-MB), and oxidative balance.

RESULTS: Compound 3b-1 showed the highest H2S release capacity and inhibited TNF-α (86%), TNF-β (82%), and nitrite (67%). In the hepatocyte model, it reduced MDA (79%), enhanced SOD (49%) and GSH (76%), and suppressed HSC activation (55%). In the myocardial model, 3b-1 attenuated mitochondrial membrane potential dissipation, decreased LDH (34%) and CK-MB (24%), and restored GSH activity (73%) while reducing MDA (48%).

DISCUSSION: The phosphorus-sulfur scaffold-based H2S donor 3b-1 demonstrates synergistic anti-inflammatory, antioxidant, and organ-protective effects, highlighting its promise as a drug candidate for treating inflammation- and oxidative stress-related disorders.

PMID:40979186 | PMC:PMC12447644 | DOI:10.3389/fchem.2025.1643663

Front Pharmacol. 2025 Sep 4;16:1566674. doi: 10.3389/fphar.2025.1566674. eCollection 2025.

ABSTRACT

BACKGROUND: Myocardial ischemia-reperfusion injury (IRI) is the major cause of primary graft dysfunction in heart transplantation, which is characterized by mitochondrial dysfunction. Hyperoside is a bioactive compound that has been reported to have pharmacological potential for cardiac and mitochondrial protection. Here, we investigated the protective effect of hyperoside during myocardial IRI and identified the underlying mechanisms.

METHODS: In this study, we established IRI in an in vivo murine heterotopic heart transplantation model and an in vitro hypoxia-reoxygenation cell model. Inflammatory responses, oxidative stress level, mitochondrial function, and cardiomyocyte apoptosis were evaluated.

RESULTS: We found that hyperoside pretreatment alleviated through reducing MDA content, LDH activity, TUNEL positive cells, serum cTnI level, Bax protein expression and the level of inflammatory cytokines, and increasing SOD activity and Bcl-2 protein expression. Furthermore, hyperoside pretreatment improved Opa1-mediated mitochondrial fusion, upregulated mitochondrial ATP content and downregulated NADP+/NADPH and GSSG/GSH ratios. Opa1 inhibitor blunted the protective effects of hyperoside. Mechanistically, Co-immunoprecipitation experiments showed the binding property between Tom70 and Opa1, siRNA knockdown, AAV-mediated loss-of-function and gain-of-function approaches suggested that hyperoside-promoted Opa1-mediated mitochondrial fusion required the upregulation of Tom70.

CONCLUSION: Collectively, we demonstrated for the first time that hyperoside administration alleviates myocardial IRI by promoting Opa1-mediated mitochondrial fusion in vivo and in vitro. The Tom70-Opa1 pathway was essential for cardioprotective effects of hyperoside treatment. The results in our study indicated that hyperoside or promotion of mitochondrial fusion might be a new potential option for the prevention and treatment of IRI in heart transplantation.

PMID:40978492 | PMC:PMC12443569 | DOI:10.3389/fphar.2025.1566674

Pol J Pathol. 2025;76(2):131-140. doi: 10.5114/pjp.2025.153974.

ABSTRACT

This study aims to elucidate the role and molecular mechanism of microRNA-21 (miR-21) in LPS-induced inflammatory injury in H9c2 cardiomyocytes. H9c2 cardiomyocytes were treated with lipopolysaccharide (LPS) to establish an in vitro model. The expression of miR-21 was quantified using RT-qPCR, while protein levels were assessed via Western blot analysis. The impact of miR-21 on inflamma-tory response, cell proliferation, and apoptosis in LPS-treated H9c2 cells was evalu-ated using ELISA, CCK-8/EdU assays, and flow cytometry. TargetScan predictions and dual-luciferase reporter assays were employed to identify potential miR-21 tar-gets. The regulatory effects of miR-21 on inflammation, proliferation, and apop-tosis in cells were further examined following transfection with phospholipase D1 (PLD1) overexpression constructs or signal transducer and activator of transcription 3 (STAT3) activation. The expression levels of miR-21, PLD1, and p-STAT3 were significantly elevated in LPS-treated H9c2 cells. Knockdown of miR-21 markedly inhibited the LPS-induced inflammatory response, enhanced cell proliferation, and reduced apoptosis in H9c2 cells. PLD1 and STAT3 were confirmed as direct targets of miR-21. Overexpression of PLD1 or activation of STAT3 significantly reversed the protective effects of miR-21 downregulation in LPS-treated H9c2 cells. Downregu-lation of miR-21 protects cardiomyocytes against LPS-induced inflammatory injury and apoptosis by inhibiting PLD1 expression and STAT3 phosphorylation.

PMID:40977551 | DOI:10.5114/pjp.2025.153974

Biol Pharm Bull. 2025;48(9):1412-1418. doi: 10.1248/bpb.b25-00185.

ABSTRACT

Adriamycin (ADR)-induced cardiotoxicity was previously shown to be attenuated by the preadministration of docetaxel (DOC-ADR), with DOC given 12 h before ADR, and may involve the inhibition of ADR-induced increases in free radical production in myocardial tissue. However, the mechanisms by which DOC suppresses the production of free radicals remain unclear. Therefore, we herein investigated the mechanisms responsible in more detail. The direct effects of DOC on free radical scavenging were examined using a primary cardiomyocyte culture system and the organic radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). To assess the indirect effects of DOC, in vivo components with radical-scavenging activities were measured after the administration of DOC. Cell viability did not improve in the DOC-ADR group, and was lower than that in the ADR group. Furthermore, DOC did not scavenge DPPH. The radical-scavenging activities of antioxidant enzymes did not significantly differ between the DOC-ADR and ADR groups. On the other hand, ceruloplasmin (CP) oxidase activity, which acts on iron ions and suppresses reactive oxygen species (ROS) production, showed a marked transient change that peaked at 12 h after DOC was given (just before the administration of ADR). Therefore, ADR-induced ROS production may have been suppressed by CP activity, which was increased by the preadministration of DOC.

PMID:40976695 | DOI:10.1248/bpb.b25-00185

Cell Signal. 2025 Sep 18;136:112144. doi: 10.1016/j.cellsig.2025.112144. Online ahead of print.

ABSTRACT

When coronary reperfusion is delayed in myocardial infarction (MI), persistent ischemic injury induces progressive loss of cardiomyocytes, ultimately resulting in pathological ventricular remodeling and heart failure. Secreted proteins may play a critical role in modulating cardiomyocyte death following MI, offering potential therapeutic targets. This study elucidated the biological function of fibroblast-secreted ADAMTSL2 in cardiomyocyte apoptosis post-MI. Elevated ADAMTSL2 levels were detected by ELISA in the serum of acute myocardial infarction patients and by immunoblotting in the infarcted myocardium of mice. Hypoxia treatment significantly upregulated ADAMTSL2 expression in neonatal rat cardiac fibroblasts (NRCFs), whereas no such hypoxic response was observed in neonatal rat cardiomyocytes (NRCMs). In vitro, overexpression of ADAMTSL2 in NRCFs attenuated oxygen-glucose deprivation (OGD)-induced apoptosis in NRCMs, whereas knockdown of ADAMTSL2 in NRCFs exacerbated cardiomyocyte apoptosis. In vivo, fibroblast-targeted overexpression of ADAMTSL2 by adenovirus 5 significantly reduced cardiomyocyte apoptosis and ameliorated adverse left ventricular remodeling post-MI. Conversely, ADAMTSL2 knockdown exacerbated infarct size and accelerated pathological remodeling. Mechanistically, ADAMTSL2 overexpression increased the expression of β-catenin in cardiomyocytes. Co-immunoprecipitation (Co-IP) assay showed that ADAMTSL2 could directly bind to LRP6 and promote its phosphorylation, leading to β-catenin stabilization and subsequent nuclear translocation. In summary, our study indicates that ADAMTSL2 protects against cardiomyocyte apoptosis and promotes cardiac repair by activating LRP6/β-catenin signaling.

PMID:40975504 | DOI:10.1016/j.cellsig.2025.112144

Bioorg Med Chem. 2025 Sep 17;131:118395. doi: 10.1016/j.bmc.2025.118395. Online ahead of print.

ABSTRACT

Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific protein kinase, whose overexpression is closely linked to heart failure and ventricular remodeling. TNNI3K inhibitors regulate the phosphorylation of serine residues in downstream cardiac troponin I (cTnI) and affect the p38 pathway to prevent ventricular remodeling and myocardial cell damage. This study designed 120 compounds based on the reported quantitative structure-activity relationships (QSAR) of TNNI3K inhibitors. Following virtual screening, 4-azaindole was identified as the optimal scaffold. Subsequent synthesis of derivatives SK1-SK5 demonstrated their protective effects on damaged cardiomyocytes. Importantly, molecular dynamics (MD) simulations confirmed that compound SK5 forms a stable complex with TNNI3K and elucidated key binding residues and their interaction modes. These findings collectively validate the rational design of TNNI3K-targeted compounds and support SK5's potential as an anti-heart failure lead candidate.

PMID:40974855 | DOI:10.1016/j.bmc.2025.118395

Crit Rev Eukaryot Gene Expr. 2025;35(6):1-10. doi: 10.1615/CritRevEukaryotGeneExpr.v35.i6.10.

ABSTRACT

Myocardial fibrosis is a critical pathological process in the progression of heart failure and other cardiovascular diseases. Kaempferol (KMP), a natural flavonoid, has antioxidant and anti-inflammatory properties. This study investigates the effects of KMP on myocardial fibrosis. Isoproterenol injection was used to establish myocardial fibrosis mouse model. Cardiac function was assessed by echocardiography. Histology analysis was conducted using Masson assay and Sirius red staining. The expression of survival of motor neuron 1 (α-SMA) and Collagen III was detected using immunohistochemistry. RNA expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cytokine release was detected using enzyme-linked immunosorbent assay. Protein expression was detected using Western blot. We found that KMP treatment improved cardiac function as well as suppressed myocardial fibrosis. Moreover, KMP treatment decreased expression of fibrosis-related genes and attenuated inflammation in fibrotic hearts. Furthermore, KMP treatment inhibited the expression of coagulation factor VII (FVII), the overexpression of which promoted inflammation response and myocardial fibrosis. In summary, KMP exerts protective effects against myocardial fibrosis via downregulating FVII. These findings suggest that KMP may be a promising therapeutic candidate for myocardial fibrosis.

PMID:40972093 | DOI:10.1615/CritRevEukaryotGeneExpr.v35.i6.10

FASEB J. 2025 Sep 30;39(18):e71046. doi: 10.1096/fj.202502567RR.

ABSTRACT

Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, characterized by myocardial inflammation, oxidative stress, and cardiac dysfunction. Chlorogenic acid (CGA), a natural polyphenol with known anti-inflammatory and antioxidant properties, is abundant in many traditional medicinal plants used for cardiovascular and inflammatory disorders. However, its cardioprotective effects in SICM and the underlying mechanisms remain unclear. An in vivo cecal ligation and puncture (CLP) model was used to induce SICM in rats, followed by CGA treatment. Cardiac function and myocardial injury markers were assessed, while NLRP3 inflammasome activation and CaMKIIα involvement were investigated using molecular docking, gene overexpression, and site-directed mutagenesis. H9c2 cardiomyocytes were treated with lipopolysaccharide (LPS) and hypoxia/reoxygenation (H/R) to establish an in vitro SICM model. Mitochondrial function and pyroptosis were evaluated using oxygen consumption rate (OCR), extracellular acidification rate (ECAR), scanning electron microscopy (SEM), and key protein expression analysis. CGA improved cardiac function, reduced myocardial injury markers, and alleviated inflammation and fibrosis in SICM rats. CGA (25 μM) improved H9c2 cell viability in LPS + H/R-induced SICM by reducing LDH, CK-MB, and cTnT levels and suppressing inflammation, oxidative stress, and pyroptosis. It preserved mitochondrial function and cristae structure. Molecular docking and functional studies confirmed CGA binds to CaMKIIα and NLRP3, inhibiting inflammasome activation via the Ca2+/CaMKIIα pathway. Mutation of the GLU60 binding site abolished CGA's protective effects both in vitro and in vivo. CGA ameliorates SICM by suppressing NLRP3 inflammasome activation and pyroptosis through the Ca2+/CaMKIIα pathway. These findings offer new insights into CGA's cardioprotective effects and highlight its potential as a therapeutic agent for SICM.

PMID:40970598 | DOI:10.1096/fj.202502567RR

J Pharmacol Exp Ther. 2025 Aug 28;392(10):103681. doi: 10.1016/j.jpet.2025.103681. Online ahead of print.

ABSTRACT

Lornoxicam is traditionally used as an anti-inflammatory and analgesic drug. Recent studies suggest that nonsteroidal anti-inflammatory drugs can influence platelet and coagulation pathways. However, the antithrombotic and cardiopulmonary protective potential of lornoxicam remains unexplored. This study addressed this gap by evaluating lornoxicam's effects on thrombosis, myocardial infarction (MI), and pulmonary embolism (PE) using in silico, in vitro, and in vivo models. Docking analysis with 16 target proteins revealed novel interactions with lornoxicam, suggesting potential antithrombotic and cardiopulmonary benefits of beyond its cyclooxygenase (COX)-mediated actions. AutoDock (version 4.2.6) was used with default parameters and empirical force field (Exhaustiveness: 8). High binding affinities (E-value > -9.0 kcal/mol) were observed for COX-1, glycoprotein IIb/IIIa, antithrombin III, COX-2, and nuclear factor kappa light chain enhancer of activated B cells (NFκB), and molecular dynamics simulations confirmed stable ligand-protein complexes. In arachidonic acid-induced platelet aggregation, lornoxicam showed concentration-dependent inhibition (77.8% at 10 μM, IC50 = 0.61 μM) compared with 94.81% inhibition by aspirin (10 μM). In ADP-induced aggregation assays, inhibition was less pronounced (23.21% at 10 μM, IC50 = 20.6 μM). Lornoxicam significantly prolonged prothrombin time, activated partial thromboplastin time, thrombin time, and clot lysis at 1, 3, and 10 μM concentrations (P < .001 vs saline). The cardioprotective potential of lornoxicam was confirmed via an isoprenaline (ISO)-induced MI model in rats, while its protective effect on PE was assessed using a self-embolus-induced PE rat model. Lornoxicam protected the heart and lung tissues of rats against histological damage and infarction by decreasing oxidative stress and inflammatory responses. This effect was due to reduced expression of NFκB, tumor necrosis factor alpha, COX-2, NOD-like receptor family, pyrin domain containing 3, and platelet-derived growth factor beta (in the lungs), as confirmed via immunohistochemical analysis, ELISA, and reverse-transcription polymerase chain reaction. This study opens a new avenue for the repurposing and prophylactic use of lornoxicam in patients more prone to thrombotic disorders. SIGNIFICANCE STATEMENT: The in silico, in vitro, and in vivo experiments in this study revealed the excellent antithrombotic potential and protective effect of lornoxicam on myocardial infarction and pulmonary embolism, even at lower doses. This study proposes that lornoxicam treatment, just like aspirin, at lower doses could be an appropriate prophylactic option in patients who are more prone to myocardial infarction and pulmonary embolism.

PMID:40967083 | DOI:10.1016/j.jpet.2025.103681

Biochem Biophys Res Commun. 2025 Sep 10;784:152613. doi: 10.1016/j.bbrc.2025.152613. Online ahead of print.

ABSTRACT

Reperfusion injury is a complex pathological process that exacerbates conditions such as myocardial infarction, stroke, and neonatal hypoxic-ischemic encephalopathy (HIE). In HIE, the reoxygenation phase amplifies the initial hypoxic insult by inducing oxidative stress, vascular dysfunction, and neuronal death via apoptosis and ferroptosis. Despite its clinical importance, the multifaceted nature of reperfusion injury poses challenges for experimental modeling and therapeutic screening. Here, we developed and refined a zebrafish hypoxia-reoxygenation platform that recapitulates key features of reperfusion injury associated with neonatal HIE, enabling both mechanistic studies and therapeutic validation with S-nitrosoglutathione (GSNO). Zebrafish larvae at 5 or 6 days post-fertilization (dpf) were subjected to varying hypoxia durations (5-20 min) followed by reoxygenation, with 6 dpf larvae exposed to 15 min hypoxia yielding a reproducible ∼50% survival at 48 h post-reoxygenation, providing an optimal baseline for intervention testing. This platform reproduces core pathophysiological outcomes including reduced survival, impaired motor behavior, neuronal loss, vasoconstriction, and diminished cerebral blood flow. GSNO (5-20 μM) was administered during early reoxygenation to assess dose-dependent effects. Treatment with 15 μM GSNO significantly improved survival, restored behavioral function, and mitigated neuronal and vascular dysfunction. Mechanistic analyses revealed that GSNO reduced caspase-3 expression, malondialdehyde (MDA) levels, and intracellular Fe2+ accumulation. These protective effects likely reflect GSNO's multifaceted mechanisms, including NO-mediated vasodilation, inhibition of apoptotic pathways, augmentation of glutathione to counter oxidative stress, and facilitation of S-nitrosation, a key post-translational modification regulating protein function and cellular signaling. Overall, this work establishes a physiologically relevant zebrafish platform for modeling reperfusion injury in neonatal HIE, demonstrating its utility for therapeutic screening and underscoring GSNO's potential as a multi-target protective agent in this setting.

PMID:40967034 | DOI:10.1016/j.bbrc.2025.152613

Cardiovasc Res. 2025 Sep 12:cvaf133. doi: 10.1093/cvr/cvaf133. Online ahead of print.

NO ABSTRACT

PMID:40966486 | DOI:10.1093/cvr/cvaf133

PLoS One. 2025 Sep 18;20(9):e0332892. doi: 10.1371/journal.pone.0332892. eCollection 2025.

ABSTRACT

BACKGROUND: Heart failure (HF) is a major cardiovascular disease with high mortality worldwide, whose pathophysiology is multifaceted. Hypoxia has emerged as a critical factor contributing to the progression of heart failure. We aimed to examine the expression and functions of LncRNA Kcnq1ot1 in hypoxia-induced cardiomyocytes in the process of HF.

METHODS: H9C2 cell model was simulated by hypoxia treatment. TUNEL, ELISA, Western Blot and qRT-PCR assay were carried out to evaluate cell pyroptosis, inflammation and dysfunction. Subsequently, we identified the direct downstream target of Kcnq1ot1 by bioinformatics analysis, RNA pull-down, double Luciferase reporter gene and other functional experiments.

RESULTS: Firstly, Kcnq1ot1 levels was revealed to be upregulated in hypoxia cells than in control cells, and miR-27b-3p showed the opposite trend. And as expected, inhibition of Kcnq1ot1 and overexpression of miR-27b-3p both protected H9C2 against hypoxia-induced pyroptosis, inflammation and dysfunction. Moreover, miR-27b-3p was proved to bind with Kcnq1ot1 and participated in Kcnq1ot1-mediated H9C2 injury under hypoxia by regulating the Wnt3a/β-Catenin/NLRP3 signaling pathway.

CONCLUSIONS: Collectively, our study demonstrated that inhibition of Kcnq1ot1 protected cardiomyocyte against hypoxia-induced injury possibly via sponging miR-27b-3p, which could be useful as biomarkers and therapeutic targets for HF patients.

PMID:40966241 | PMC:PMC12445483 | DOI:10.1371/journal.pone.0332892

Curr Neuropharmacol. 2025 Sep 15. doi: 10.2174/011570159X394212250825051955. Online ahead of print.

ABSTRACT

Myocardial Infarction (MI) is a severe cardiovascular event, causing not only substantial damage to the heart but also potentially exerting a profound impact on brain function through a complex cardiac-brain interaction mechanism. The pathological process of MI encompasses myocardial cell necrosis, inflammatory cell infiltration, and the release of a substantial amount of inflammatory mediators. Through the bloodstream, these myocardial mediators may traverse the Blood-Brain Barrier (BBB), eliciting a neuroinflammatory response that can lead to cognitive dysfunction. This article proposes a critical research direction: investigating whether MI mediates the effects of myocardial- derived mediators on the permeability of the BBB, as well as the potential consequences of these mediators on cognitive functions. This review is aimed at triggering future research to elucidate the underlying mechanisms governing heart-brain interactions after MI in order to facilitate the development of more effective cognitive protection strategies for patients with MI.

PMID:40965068 | DOI:10.2174/011570159X394212250825051955

medRxiv [Preprint]. 2025 Sep 11:2025.08.22.25333921. doi: 10.1101/2025.08.22.25333921.

ABSTRACT

BACKGROUND: ADRB1 and ADRB2, encoding cardiac myocyte β1- and β2-adrenergic receptors (ARs) that mediate pathologic myocardial remodeling in response to chronically increased signaling, contain N-terminus haplotype variants capable of influencing agonist- or biased ligand-induced receptor internalization that uncouples canonical signaling and initiates EGFR/ERK1/2 cardioprotection.

METHODS: In two heart failure (HF) clinical trial genetic substudies we investigated effects of internalizing vs. internalization-resistant ADRB1/ADRB2 haplotypes on clinical or biomarker responses to the biased ligand β-blocker bucindolol vs. placebo or vs. the nonbiased β1-antagonist metoprolol, and in haplotyped isolated human heart preparations we measured ERK1/2 activation in response to these same interventions.

RESULTS: In subjects with ≥3 internalizing ADRB1+ADRB2 haplotypes (6.7% subcohort) placebo treatment was associated with fewer clinical events compared to subjects with internalization-resistant haplotypes (Odds Ratio (OR) 0.28, 95% CI (0.10, 0.82)). In contrast, placebo treatment in subjects with ≥3 internalization-resistant haplotypes (70% subcohort) was associated with more clinical events in comparison to subjects with internalizing haplotype counterparts (OR 1.64 (1.46, 1.84)). Bucindolol treatment was equal to placebo in the ≥3 internalizing subcohort, but was superior to placebo in the internalization-resistant subcohort (bucindolol vs. placebo OR 0.49 (0.41, 0.58)). In subjects with all 4 haplotypes internalization-resistant (25% subcohort), bucindolol vs. placebo reduced time to first event rates by 62.3±17.5% (P <0.01, 1.68±0.34 fold > the all-haplotypes parent population and additive to 1.92±0.58 fold when the ADRB1 haplotype contained Arg389 rather than Gly389). The same bucindolol vs. placebo pattern was observed for NT-proBNP or norepinephrine reduction vs. metoprolol. In these comparisons ADRB2 and ADRB1 haplotypes behaved similarly, and although the haplotypes differed in frequency between Black and non-Black subjects, within haplotypes there were no by-race differences in therapeutic effects. Bucindolol but not metoprolol activated ERK1/2 signaling in isolated ventricular preparations with ≥3 internalization-resistant haplotypes.

CONCLUSIONS: 1) Both β1- and β2-AR haplotypes regulate therapeutic responses in HF; internalizing species confer protection against clinical events in placebo-treated subjects, while in internalization-resistant haplotypes the biased ligand β-blocker bucindolol but not the non-biased ligand metoprolol is associated with favorable effects. 2) The biased ligand cardioprotective effect may be related to internalization-dependent or -independent ERK1/2 activation.

PMID:40963743 | PMC:PMC12440051 | DOI:10.1101/2025.08.22.25333921

Circ Res. 2025 Sep 26;137(8):1117-1132. doi: 10.1161/CIRCRESAHA.125.326758. Epub 2025 Sep 3.

ABSTRACT

BACKGROUND: In response to cardiac injury the mammalian heart undergoes ventricular remodeling to maintain cardiac function. These changes are initially considered compensatory, but eventually lead to increased cardiomyocyte apoptosis, reduced cardiac function and fibrosis which are important contributors to the development of heart failure. The small GTPase Sept4 (Septin4) has previously been implicated in the regulation of regeneration and apoptosis in several organs. However, the role of Sept4 in regulating the response of the heart to stress is unknown.

METHODS: Ten-week-old wild-type (WT) and Sept4 knockout mice were subjected to transverse aortic constriction to induce cardiac injury. Genotype-dependent differences were investigated at baseline and at 1- and 4-week postinjury time points. To definitively establish the fibroblast-specific cardioprotective effects of Sept4, we generated a fibroblast-specific Sept4 conditional knockout model.

RESULTS: Under homeostatic conditions Sept4 knockout mice showed normal cardiac function comparable with WT controls. In response to transverse aortic constriction, WT mice developed reduced cardiac function and heart failure, accompanied by an increase in cardiomyocyte apoptosis. In contrast, knockout mice were protected against injury with maintenance of normal cardiac function and reduced levels of cardiomyocyte apoptosis. Both at baseline and after transverse aortic constriction, knockout hearts exhibited decreased levels of cardiac extracellular matrix deposition and fibrosis compared with WT controls. In support of these data, the level of myofibroblast activation was lower after injury in knockout mice. Furthermore, the knockout group showed higher levels of cardiac compliance and improved diastolic function compared with WT controls. Mechanistically, we identified reduced fibrosis development due to alterations in calcineurin-dependent signaling in fibroblasts. These results were further verified in fibroblast-specific conditional Sept4 knockout mice subjected to cardiac pressure overload.

CONCLUSIONS: We identified Sept4 as an important regulator of extracellular matrix remodeling in the heart. Sept4 controls the conversion of fibroblast to myofibroblast through calcineurin-dependent mechanisms.

PMID:40960950 | DOI:10.1161/CIRCRESAHA.125.326758