Protección miocárdica

Ann Clin Lab Sci. 2025 Jul;55(4):481-495.

ABSTRACT

OBJECTIVE: To investigate the effect of exosomal miR-98-5p derived from bone marrow mesenchymal stem cells (BMSCs) on cardiomyocyte injury in acute myocardial infarction (AMI) and analyze its mechanism of action.

METHODS: An AMI model in rats was established via ligation of the left anterior descending (LAD) coronary artery. Cardiac systolic function was assessed via echocardiography. Histopathological alterations in myocardial tissue were evaluated by hematoxylin and eosin (HE) staining, while the extent of myocardial infarction was determined through triphenyltetrazolium chloride (TTC) staining. Serum levels of CK-MB, cTnT, and LDH were quantified through ELISA. An AMI cell model was established by subjecting H9C2 cardiomyoblasts to hypoxic conditions. Exosomes were isolated from BMSCs, and their effects on cardiomyocyte injury were investigated. Cellular autophagy levels were examined via western blot (WB). The regulatory interplay between miR-98-5p and E2F6 was validated via a dual-luciferase reporter (DLR) assay.

RESULTS: In comparison to the Sham group, myocardial tissue in rats with AMI exhibited significant structural damage, accompanied by reduced autophagic activity and reduced expression of miR-98-5p. In comparison to the AMI + phosphate-buffered saline (PBS) group, treatment with BMSCs-derived exosomes (BMSCs-exo) markedly improved cardiac function and further enhanced autophagy in AMI rats. In vitro, cells subjected to hypoxic conditions displayed diminished viability and proliferative capacity, increased apoptosis, impaired autophagy, and decreased miR-98-5p expression relative to the control group. However, administration of BMSCs-exo restored miR-98-5p expression, mitigated cellular injury, and promoted autophagic activity. Notably, these protective influences were reversed by the addition of the autophagy inhibitor 3-methyladenine (3-MA). DLR assays confirmed a direct regulatory interaction between miR-98-5p and E2F6. Suppression of miR-98-5p resulted in the upregulation of E2F6, thereby attenuating the reparative effects of BMSCs-exo on myocardial tissue and inhibiting autophagy.

CONCLUSION: BMSCs-exo miR-98-5p ameliorates AMI-induced myocardial injury by regulating cardiomyocyte autophagy through targeting E2F6.

PMID:40962448

J Am Coll Cardiol. 2025 Sep 23;86(12):892-906. doi: 10.1016/j.jacc.2025.07.027.

ABSTRACT

BACKGROUND: Intraoperative hypotension is associated with cardiovascular complications after major noncardiac surgery, but randomized trials assessing whether intensive blood pressure management during surgery can reduce these complications have shown inconsistent results.

OBJECTIVES: The purpose of this study was to determine whether intensive intraoperative blood pressure management reduces the incidence of a composite of cardiovascular complications within 30 days after major abdominal surgery.

METHODS: In this investigator-initiated parallel-group trial, patients at 3 Chinese sites were randomly assigned (1:1) to intensive blood pressure management targeting intraoperative MAP ≥80 mm Hg (intensive strategy group) or conventional management targeting intraoperative MAP ≥ the higher of 65 mm Hg or 60% of preoperative baseline pressure (conventional strategy group). We included patients aged ≥45 years who had known cardiovascular disease or cardiovascular risk factors and were scheduled for inpatient abdominal surgery expected to last at least 2 hours. The primary outcome was a composite of myocardial injury or infarction, new-onset clinically important arrhythmias, acute heart failure, stroke, cardiac arrest, and all-cause death within 30 days of surgery.

RESULTS: Between June 30, 2020, and September 23, 2022, 1,500 patients were enrolled, of whom 1,477 were included in the modified intention-to-treat population (739 in the intensive strategy group and 738 in the conventional strategy group). Patients assigned to intensive intraoperative blood pressure management experienced a lower burden of hypotension exposure, as assessed by several measures. For example, the median cumulative duration of MAP <65 mm Hg was 1 minute (Q1-Q3: 0-7 minutes) in the intensive strategy group, compared with 8 minutes (Q1-Q3: 0-20 minutes) in the conventional strategy group. The primary composite outcome occurred in 107 of 739 patients (14.5%) in the intensive strategy group and 100 of 738 patients (13.6%) in the conventional strategy group (relative risk: 1.07; 95% CI: 0.83-1.38; P = 0.61).

CONCLUSIONS: In high-risk patients having major abdominal inpatient surgery, intensive intraoperative blood pressure management targeting a mean arterial pressure ≥80 mm Hg did not reduce the incidence of cardiovascular events compared with the conventional target of ≥65 mm Hg and 60% of the preoperative baseline.

PMID:40962376 | DOI:10.1016/j.jacc.2025.07.027

FASEB J. 2025 Sep 30;39(18):e71033. doi: 10.1096/fj.202501598R.

ABSTRACT

Myocardial ischemia/reperfusion injury (MI/R) remains a major challenge in cardiac transplantation, leading to early graft dysfunction or primary nonfunction, and eventually death. This study explores the role of annexin A4 (ANXA4), a calcium-dependent phospholipid-binding protein, in MI/R pathogenesis and investigates its underlying mechanisms. In C57BL/6J mice, ANXA4 expression was moderately increased following MI/R (induced by 45-min occlusion/24 h reperfusion) (mRNA: sham vs. MI/R = 1.00 vs. 2.42, p < 0.01; protein: 1.00 vs. 2.39, p < 0.05). To assess its functional role, AAV9 particles (1 × 1011 viral genomes per mouse) carrying ANXA4 encoding fragments were intravenously injected into mice 4 weeks before the surgery. The forced elevation of ANXA4 reduced IR-induced myocardial infarction from 41.22% to 18.23%, lowered the ventricular arrhythmias score from 10.83 to 6.00, and creatinine kinase-myocardial band (CK-MB) activity from 450 to 268 U/L. ANXA4 overexpression also inhibited cardiomyocyte apoptosis, inflammation, and oxidative stress. In vitro, ANXA4 overexpression mediated by pcDNA3.1 vector protected HL-1 mouse cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cell damage. Further high-throughput transcriptomics illustrated that ANXA4 upregulation significantly suppressed the expression of the receptor for advanced glycosylation end products (RAGE; Log2 Fold change = -3.19, p < 0.05). Mechanistically, ANXA4 repressed the transcription of RAGE by dampening the nuclear translocation of NFκB p50. Collectively, this study demonstrates that ANXA4 is upregulated in the mouse myocardium post MI/R as a compensatory response, and its overexpression alleviates MI/R- and OGD/R-induced cardiomyocyte injury by preventing NFκB p50 from binding to and initiating transcription of RAGE.

PMID:40960915 | DOI:10.1096/fj.202501598R

JAMA Cardiol. 2025 Sep 17:e253043. doi: 10.1001/jamacardio.2025.3043. Online ahead of print.

ABSTRACT

IMPORTANCE: Animal studies and meta-analysis of human observational data suggest that pneumococcal polysaccharide vaccination (PPV) could be protective against atherosclerosis; however, to the authors' knowledge, no randomized clinical trial has been conducted.

OBJECTIVE: To determine whether pneumococcal vaccination (Pneumovax [Merck Sharp & Dohme Corp]) decreases the composite primary outcome of fatal and nonfatal acute coronary syndrome and ischemic stroke in people at increased risk, with an average follow-up of 7 years after immunization.

DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, placebo-controlled, parallel-arm randomized clinical trial conducted at 6 centers across Australia. Participants were community-dwelling adults 55 to 60 years of age at baseline in 2016 to 2017, with at least 2 risk factors (obesity, hypertension, or hypercholesterolemia) for cardiovascular disease (CVD) but no prior CVD event or indication for early pneumococcal vaccination. Data were analyzed from February 2023 to December 2024 using competing risk proportional hazards regression models, stratified by sex and center.

INTERVENTIONS: Participants received either 23-valent PPV (PPV23) or placebo (saline).

MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of fatal and nonfatal myocardial infarction or ischemic stroke, ascertained via electronic medical records from emergency department, admitted patient, and mortality data collections using International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes.

RESULTS: A total of 4725 participants (mean [SD] age, 58.0 [1.7] years; 2433 male [52%]) were included in this study. There was no significant difference in the primary outcome (58 of 2366 events in the active PPV23 group compared with 64 of 2357 events in the control group, hazard ratio, 0.90; 95% CI, 0.63-1.28; P = .57). Similarly, no significant differences occurred in the exploratory outcomes of all-cause mortality, all-cause hospital presentations, and CVD-related hospital procedures. These results are tempered by the lower than expected event rate leading to low power.

CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial found that PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke, although the study was underpowered.

TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12615000536561.

PMID:40960793 | PMC:PMC12444640 | DOI:10.1001/jamacardio.2025.3043

J Physiol Investig. 2025 Sep 17. doi: 10.4103/ejpi.EJPI-D-25-00032. Online ahead of print.

ABSTRACT

The complex pathogenesis of myocardial ischemia-reperfusion (I/R) injury is a major factor influencing clinical prognosis. It has been confirmed that microRNAs are involved in myocardial I/R injury, and that pyroptosis is closely associated with its underlying mechanisms. However, the specific mechanism by which miR-193b-3p inhibits cell death and alleviates myocardial I/R injury remains unclear. This study aimed to investigate whether miR-193b-3p can inhibit pyroptosis and protect injured myocardium by targeting the Gasdermin-D (GSDMD)/Nucleotide-binding oligomerization domain-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling axis, thereby offering a potential therapeutic strategy for myocardial I/R injury. Through bioinformatics analysis, pyroptosis-related signaling pathways and key genes involved in myocardial I/R injury were identified. A myocardial I/R injury model was established, and pathological changes in myocardial tissue were evaluated using hematoxylin and eosin staining. A dual-luciferase reporter assay was conducted to verify the targeting relationship between miR-193b-3p and GSDMD. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were employed to detect mRNA and protein expression levels of miR-193b-3p, GSDMD, and NLRP3. The role of miR-193b-3p in myocardial I/R injury was comprehensively evaluated based on cardiac troponin I levels and the rate of myocardial pyroptosis. The findings confirmed that miR-193b-3p inhibited GSDMD expression, attenuated pathological changes in rat myocardium, downregulated NLRP3 and other pyroptosis-related proteins, and reduced both myocardial pyroptosis and serum cardiac troponin I levels.

PMID:40960060 | DOI:10.4103/ejpi.EJPI-D-25-00032

J Physiol Investig. 2025 Sep 17. doi: 10.4103/ejpi.EJPI-D-25-00033. Online ahead of print.

ABSTRACT

Sepsis-induced myocardial dysfunction (SIMD) is a severe consequence of systemic infection, primarily driven by mitochondrial dysfunction, inflammation, and pyroptosis. Sonlicromanol, a mitochondrial redox-modulating therapeutic agent, has shown promise in preserving mitochondrial function, but its role in sepsis-induced cardiac injury remains unclear. This study evaluates the protective effects of sonlicromanol in a rat model of sepsis-induced cardiac dysfunction, with a focus on mitochondrial dynamics, mitophagy, and inflammasome-pyroptosis pathways. Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Sonlicromanol (50 mg/kg/day) was administered intraperitoneally for 2 weeks before CLP. Rats were divided into five groups: (1) Control, (2) CLP, (3) CLP + sonlicromanol, (4) CLP + Mdivi-1 (mitophagy inhibitor), and (5) CLP + sonlicromanol + Mdivi-1. Cardiac function was evaluated via catheter-based pressure analysis, including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and left ventricular developed pressure (LVDP). Myocardial injury, histopathology, inflammasome-pyroptosis activation, mitophagy, and mitochondrial dynamics were assessed via enzyme-linked immunosorbent assay, H and E staining, Western blot, and mitochondrial fluorometric assays. CLP-induced septic rats showed reduced LVSP and LVDP, along with elevated LVEDP, cardiotroponin, and B-type natriuretic peptide, and significant myocardial damage. Pyroptosis markers (nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3, cleaved caspase-1, gasdermin-D, interleukin-1 β, and lactate-dehydrogenase) were elevated, while mitophagy markers (PTEN-induced kinase 1 and Parkin) and mitochondrial function (membrane potential and adenosine triphosphate levels) declined. Sonlicromanol significantly improved cardiac function and injury markers, suppressed pyroptosis, restored mitochondrial dynamics (increased mitofusin-2, modulated dynamin-related protein 1), enhanced mitophagy, and improved mitochondrial function. Mdivi-1 co-treatment attenuated these effects, indicating a role for mitochondrial dynamics and mitophagy in sonlicromanol's efficacy. Sonlicromanol ameliorates SIMD by modulating mitochondrial homeostasis and inhibiting pyroptosis. These findings support sonlicromanol as a potential therapy for sepsis-related cardiac injury.

PMID:40960053 | DOI:10.4103/ejpi.EJPI-D-25-00033

Sci Rep. 2025 Sep 16;15(1):32098. doi: 10.1038/s41598-025-17224-6.

ABSTRACT

Myocardial infarction (MI) remains the leading cause of death worldwide. We previously found that a specific population of human fetal cardiac fibroblasts (fCFs), which express vascular cell adhesion molecule 1 (VCAM1), have cardioprotective effects after MI, inducing reparative cardiac lymphangiogenesis. This study investigated whether adult cardiac fibroblasts (aCFs), which are more feasible for autologous transplantation, differ in surface marker expression and lymphangiogenic potential compared to fCFs. Furthermore, we examined whether aCFs could be exogenously manipulated to acquire fCF-like lymphangiogenic potential and serve as a cell therapy for MI and MI-associated heart failure. In vivo MI models (rat and mouse) and in vitro coculture assays with lymphatic endothelial cells were conducted. We found that TNF-α and IL-4 stimulation induced aCFs to express VCAM1 via NF-κB and STAT6 signaling, yielding a subpopulation termed adult VCAM1+ cardiac fibroblasts (aVCFs). These aVCFs, distinct from myofibroblasts, expressed CD90 and improved cardiac function post-MI. Adrenomedullin (ADM) was identified as a key paracrine effector, and its knockdown attenuated the pro-lymphangiogenic and cardioprotective effects of aVCFs. Our findings demonstrate that aVCFs promote cardiac lymphangiogenesis and protect cardiac function following MI, highlighting their potential as an autologous cell therapy.

PMID:40957875 | PMC:PMC12441115 | DOI:10.1038/s41598-025-17224-6

Spectrochim Acta A Mol Biomol Spectrosc. 2025 Sep 12;346:126933. doi: 10.1016/j.saa.2025.126933. Online ahead of print.

ABSTRACT

Myocardial ischemia-reperfusion injury (MIRI) presents significant clinical challenges due to its complex multimechanistic pathophysiology. Although hydrogen sulfide (H₂S) and carbon monoxide (CO) exhibit individual cardioprotective effects via anti-apoptotic/anti-inflammatory pathways, their synergistic potential remains underexplored due to the absence of delivery systems enabling spatiotemporal co-regulation of these gasotransmitters. Current approaches face technical limitations in simultaneous gas quantification and therapeutic delivery, often compromising treatment efficacy through gas leakage during monitoring. To address these challenges, we developed HSCOD, a theranostic donor featuring cysteine-activated H₂S release followed by light-controlled CO generation, while incorporating self-reporting fluorescence for real-time gas tracking. In cellular and zebrafish MIRI models, dual-gas co-delivery demonstrated superior efficacy to monotherapies, significantly reducing apoptosis, pyroptosis, oxidative stress, and inflammation through coordinated cardioprotection. This study further validated the "gas waltz therapy" concept of spatiotemporally orchestrated gas interactions, with HSCOD serving as both a therapeutic agent and research tool for decoding gas crosstalk in multifactorial diseases. The platform overcomes critical limitations in gas therapy by integrating controlled release with real-time tracking, advancing targeted treatment strategies for complex pathologies.

PMID:40957205 | DOI:10.1016/j.saa.2025.126933

Anesth Analg. 2025 Oct 1;141(4):706-717. doi: 10.1213/ANE.0000000000007290. Epub 2024 Nov 13.

ABSTRACT

BACKGROUND: Failing heart is more likely to suffer from myocardial ischemia/reperfusion (I/R) injury. This poses a great challenge for anesthesiologists in managing patients with heart failure during major surgery. Evidence from animal studies suggests that the delta-opioid receptor (DOR) contributes to alleviating acute myocardial injuries. However, little is known regarding the cardioprotective effects of cardiac DOR in patients with chronic heart failure. This study aimed to examine DOR expression in failing hearts and explore how DOR regulates the Janus kinase signal transducer and activator of the transcription-3 (JAK/STAT3) pathway to mediate morphine-induced cardio protection in heart failure.

METHODS: We measured the DOR protein levels in human and rat heart tissues with chronic heart failure. To investigate the cardioprotective role of DOR, we administered the DOR-specific antagonist, naltrindole (NTD), and JAK2 inhibitor, AG490, before morphine preconditioning (MPC) in an isolated perfusion model of myocardial I/R injury in postinfarcted failing rat heart. We examined the infarct size, cardiac enzymes, cardiac function, cardiomyocyte apoptosis, apoptosis-related proteins, and STAT3 phosphorylation in the heart.

RESULTS: The protein levels of DOR were significantly elevated in the myocardial tissues of humans and rats with chronic heart failure, by 1.4-fold (mean difference 0.41; 95% confidence interval [CI], 0.04-0.78; P = .032) and 2.3-fold (mean difference 1.26; 95% CI, 0.25-2.28; P = .009), respectively, compared to control tissues. Disease severity positively correlated with DOR expression (human: R2 = 0.316, P = .004; rat: R2 = 0.871, P = .021). Blocking DOR substantially reversed the cardioprotective effects of MPC in postinfarcted rat hearts, increasing the mean (standard deviation) percentage of infarct size from 15.0 (3.9)% to 30.8 (7.7)% (P < .001). Similarly, AG490 inhibited MPC restoration of cardiomyocyte apoptosis (33.3 [4.2]% vs 16.6 [3.4]%; P < .001). Both NTD and AG490 markedly suppressed STAT3 phosphorylation by 60.1% (mean difference 0.60; 95% CI, 0.27-0.93; P = .002) and 44.1% (mean difference 0.44; 95% CI, 0.06-0.83; P = .027), respectively, and also lowered the Bcl-2/Bax ratio by 85.5% (mean difference 0.86; 95% CI, 0.28-1.43; P = .006) and 68.2% (mean difference 0.68; 95% CI, 0.51-0.85; P < .001) respectively in heart tissues at the end of reperfusion.

CONCLUSIONS: DOR protein levels increased in failing hearts of both humans and rats. Blocking cardiac DOR selectively reduced morphine-induced cardio protection by inhibiting the JAK2/STAT3 pathway. These findings indicate that cardiac DOR is a potential therapeutic target for protecting against heart failure due to I/R injury.

PMID:40956785 | DOI:10.1213/ANE.0000000000007290

Adv Healthc Mater. 2025 Sep 15:e02975. doi: 10.1002/adhm.202502975. Online ahead of print.

ABSTRACT

Typically occurring in individuals with a genetic predisposition, long QT syndrome (LQTS) is characterized by prolonged ventricular repolarization (QT interval prolongation) and susceptibility to tip torsion, ventricular tachycardia, ventricular fibrillation, and sudden cardiac death. Currently, treatment options for LQTS include medication and surgery, but these may cause patient discomfort and disease recurrence. In this study, using biocompatible carrier-free nanomachine-based flexible bubbles are proposed to deliver phycocyanin (PC) for heart protection associated with electrophysiological stability in LQTS in vivo in mice. To form the structures, l-arginine (L-Arg) is polymerized with PC through electrostatic interactions, and Au is sputtered onto one side of the surface of L-arg/PC, functioning as a trigger for generating nitric oxide (NO) in the in vivo microenvironment. The asymmetrically released NO cargo provided a means of improving heart function and arrhythmia by delivering PC, and acted as a propellant for transporting the nanomachine to the target site. After accumulating at the site of heart damage, the nanomachines are triggered by reactive oxygen species (ROS). The accumulated nanomachines provided considerable diffusion of PC, which attenuated heart damage. The nanomachines, with ROS-induced targeting and delivery of PC, have immense potential for providing heart protection by modulating myocardial gap junction proteins and the hypoxic environment, and by ameliorating electrical remodeling in LQTS, and therefore may support future clinical testing.

PMID:40954980 | DOI:10.1002/adhm.202502975

Naunyn Schmiedebergs Arch Pharmacol. 2025 Sep 15. doi: 10.1007/s00210-025-04602-0. Online ahead of print.

NO ABSTRACT

PMID:40952477 | DOI:10.1007/s00210-025-04602-0

World J Stem Cells. 2025 Aug 26;17(8):111497. doi: 10.4252/wjsc.v17.i8.111497.

ABSTRACT

Bone marrow-derived mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (ADSCs), two principal subtypes of mesenchymal stem cells with multilineage regenerative potential, have emerged as promising therapeutic strategies for various diseases. While BMSCs and ADSCs exhibit distinct functional profiles tailored to different therapeutic applications, emerging evidence suggests that ADSCs may be a more promising approach for treating ischemic pathologies, including myocardial infarction, ischemic stroke, and peripheral artery disease, in comparison with BMSCs. However, the precise molecular mechanisms by which ADSCs enhance the therapeutic outcomes in these diseases remain poorly understood. In this editorial, we comment on the article by Li et al, which systematically compares the therapeutic efficacy of ADSCs and BMSCs derived from the same elderly patients with coronary heart disease and explores the underlying mechanism from a metabolic perspective. This study proposes that the metabolite L-arginine in ADSCs isolated from elderly patients promotes angiogenesis and protects against apoptosis in a hypoxic and ischemic microenvironment, thereby enhancing myocardial repair following infarction. These findings not only highlight the metabolic plasticity of ADSCs but also position L-arginine as a pivotal therapeutic effector in coronary heart disease. Given the novel and crucial role of L-arginine in ischemic heart diseases, further exploration of L-arginine in ADSCs (particularly those derived from elderly individuals) is essential, including its roles in angiogenesis, cell death, and the potential therapeutic implications in other ischemic pathologies. Additionally, further investigation into additional metabolites in ADSCs is warranted to enhance the therapeutic potential of ADSCs in ischemic pathologies.

PMID:40951708 | PMC:PMC12427081 | DOI:10.4252/wjsc.v17.i8.111497

Drug Des Devel Ther. 2025 Sep 9;19:7929-7946. doi: 10.2147/DDDT.S515053. eCollection 2025.

ABSTRACT

Idebenone, a short-chain analog of coenzyme Q10 with a hydroxydecyl side chain, is known to activate mitochondrial function by transferring electrons to the electron transport chain complex III, thereby promoting adenosine triphosphate production. Numerous clinical trials have demonstrated the effectiveness of idebenone in the treatment of neurological diseases. Interestingly, emerging evidence suggests that idebenone may also have beneficial effects beyond neurological conditions through disrupting mitochondrial membrane potential, inducing mitochondrial apoptosis, promoting mitophagy attenuating ferroptosis, reducing reactive oxygen species and lipid peroxidation, etc. This study aims to comprehensively review the clinical potential of idebenone in various fields, including cancers (such as breast cancer, melanoma, glioblastoma, neuroblastoma, hepatocellular carcinoma, prostatic carcinoma and pancreatic carcinoma), cardiovascular diseases (including atherosclerosis, hypertension, myocardial infarction and heart failure), diabetes mellitus, liver diseases, urogenital diseases, sepsis, and other diseases. The findings highlight the potential of idebenone as a promising therapeutic option for the prevention and management of these condition, which need to be validated in more clinical trials.

PMID:40951694 | PMC:PMC12433227 | DOI:10.2147/DDDT.S515053

Food Sci Nutr. 2025 Sep 12;13(9):e70937. doi: 10.1002/fsn3.70937. eCollection 2025 Sep.

ABSTRACT

Exhaustive physical exercise, while promoting cardiovascular fitness, can paradoxically lead to excessive oxidative stress, systemic fatigue, and myocardial injury. Despite increasing awareness of exhaustion exercise myocardial damage, effective preventive strategies remain limited. Natural bioactive compounds with antioxidant and antiapoptotic properties have gained attention as potential interventions. Among them, triterpenoids derived from Ganoderma lucidum triterpenoids (GLTs) are notable for their potent free radical scavenging and cytoprotective effects. However, their cardioprotective potential under conditions of exhaustion exercise oxidative stress has not been fully elucidated. This study explores the antifatigue potential of GLTs and elucidates their underlying mechanisms through the establishment of a mouse model of exhaustion exercise via exhaustive treadmill running. This study showed that GLTs significantly alleviated exhaustion exercise by reducing serum fatigue biomarkers (CK, BUN, and LDH) and improving myocardial histopathological conditions. GLTs enhanced antioxidant capacity by decreasing MDA levels, increasing SOD and CAT activities, and elevating GSH content, thereby mitigating oxidative stress. Additionally, GLTs regulated apoptosis by downregulating Bax and Caspase-3 expression, upregulating Bcl-2 levels, and reducing the Bax/Bcl-2 ratio. Mechanistically, these effects were associated with activation of the Keap1/Nrf2/HO-1 signaling pathway. Collectively, this study provides new insights into the context-specific role of GLTs in protecting against exhaustion exercise myocardial injury. Our findings highlight the therapeutic potential of GLTs as a natural antioxidant strategy for mitigating oxidative stress, delaying fatigue, and preserving cardiac function under conditions of intensive physical exertion.

PMID:40951591 | PMC:PMC12431855 | DOI:10.1002/fsn3.70937

Narra J. 2025 Aug;5(2):e2245. doi: 10.52225/narra.v5i2.2245. Epub 2025 Apr 22.

ABSTRACT

Myocardial infarction (MI) is the leading cause of mortality worldwide. During MI, cardiomyocyte necrosis and inflammation are crucial in the post-MI cardiac remodeling process, including pyroptosis. Although colchicine is a well-known anti-inflammatory drug that has been clinically studied in the context of MI, its role in cardiac pyroptosis remains unclear. The aim of this study was to investigate the role of colchicine in pyroptosis in vitro, using CoCl2-induced H9c2 cells. Prior to the primary experiment, the hypoxic model in H9c2 cells was optimized by evaluating hypoxia-inducible factor-1 alpha (HIF-1α) expression and viability in cells exposed to various concentrations of CoCl2 at different time intervals. Subsequently, an in vitro hypoxia model was established by treating H9c2 cells with CoCl2 (600 µM), with or without colchicine (1 µM), for 3 hours. Flow cytometry was used to measure the expression of nuclear factor-kappa beta (NF-κB), interleukin 18 (IL-18), caspase-1, and HIF-1α in pyroptotic cells. Immunofluorescence was used to assess caspase-1 localization and its colocalization with propidium iodide during late-stage pyroptosis. Our data indicated that CoCl2-induced hypoxia significantly upregulated NF-κB, caspase-1, and IL-18 expression, and increased pyroptotic cell death in H9c2 cells. Colchicine treatment attenuated these effects, leading to a marked reduction in NF-κB, caspase-1, and IL-18 expression in hypoxic cells. Colchicine treatment significantly decreased the number of late pyroptotic cells. The protective effect of colchicine was more pronounced in late hypoxia (24-hour) setting compared to early hypoxia (3-hour). These findings suggest that colchicine attenuates cardiac pyroptosis in hypoxic H9c2 cells, as evidenced by the significant downregulation of key proteins involved in this pathway, including NF-κB, caspase-1, and IL-18. This protective effect appeared to be more effective in late hypoxia.

PMID:40951489 | PMC:PMC12425549 | DOI:10.52225/narra.v5i2.2245

Cureus. 2025 Aug 12;17(8):e89935. doi: 10.7759/cureus.89935. eCollection 2025 Aug.

ABSTRACT

Intravascular lithotripsy (IVL) delivers acoustic shockwaves to fracture coronary calcifications and optimize stent expansion, yet side branch (SB) occlusion after IVL is rarely documented. We report the case of an 80-year-old man with prior stents in the distal right coronary and proximal left circumflex arteries who underwent elective percutaneous coronary intervention for 75% proximal left anterior descending artery (LAD) stenosis supplying four diagonal branches: the first (D1), second (D2), third (D3), and fourth (D4) diagonal branches. The instantaneous wave-free ratio was 0.82 and the fractional flow reserve was 0.77, both indicating ischemia. Optical coherence tomography (OCT) demonstrated severe, long calcification (calcification score 4; maximum arc 330°; thickness 12.1 mm; length 38.2 mm; minimum lumen area 1.46 mm²), and IVL was selected over rotational atherectomy or scoring balloon angioplasty due to high calcification score and wire bias considerations. Eight cycles of IVL with a 2.5/12 mm balloon were applied from the D4 bifurcation to proximal LAD, followed by eight cycles with a 3.0/12 mm balloon, increasing the minimum lumen area to 3.31 mm². After pre-dilation with a 2.5/13 mm scoring balloon distally and a 3.0/15 mm non-compliant balloon proximally, a 2.5/38 mm everolimus-eluting stent was implanted, and the proximal segment was post-dilated with a 3.0/15 mm non-compliant balloon. Immediately after post-dilation, the patient developed chest pain and ST-segment elevation; angiography showed new occlusion of the third diagonal branch (D3, thrombolysis in myocardial infarction (TIMI) 0) and flow reduction in the first diagonal branch (D1) from TIMI 3 to TIMI 1, while all other branches maintained TIMI 3 flow. Wire recrossing and kissing balloon inflation (1.5/10 mm semi-compliant in D3, 3.0/15 mm non-compliant in the main vessel) restored TIMI 3 flow in D3 and relieved symptoms, whereas D1 remained TIMI 1 but asymptomatic. No protective wiring had been performed initially as the affected SB was <1.5 mm, but the subsequent ischemic event indicated it should be considered a significant branch. Angiography before and after IVL showed no change suggestive of SB risk, whereas OCT performed immediately after IVL revealed new protrusion of fractured calcifications into the D1 and D3 ostia, which was considered the cause of the subsequent side branch occlusion. IVL-related SB occlusion is an extremely rare complication in the literature, but meticulous pre-procedural OCT assessment and consideration of protective wiring in high-risk bifurcation lesions may help predict and prevent this event.

PMID:40951199 | PMC:PMC12425836 | DOI:10.7759/cureus.89935

FASEB Bioadv. 2025 Sep 12;7(9):e70049. doi: 10.1096/fba.2025-00187. eCollection 2025 Sep.

ABSTRACT

Myocardial infarction remains one of the leading causes of mortality. Reperfusion of the infarcted myocardium restores blood flow and reduces primary ischemic injury. However, despite its protective function, reperfusion is also associated with several deleterious outcomes that can result in ischemia-reperfusion (I/R) injury to cardiac tissue. Although negative outcomes such as reactive oxygen species generation are strongly associated with I/R injury, cardiac energy metabolism is also greatly disrupted. Furthermore, previous studies have shown that the restoration of normal fuel oxidation in the myocardium regulates the extent of contractile recovery. A better understanding of the pathophysiological mechanisms underlying I/R injury may allow us to develop new treatments that limit the negative aspects of the process. In this study, we examined the role played by GCN5L1, a protein implicated in the regulation of energy metabolism, in I/R injury. We demonstrate that cardiac-specific loss of GCN5L1 promotes the inhibitory phosphorylation of pyruvate dehydrogenase in vitro and in vivo, a process likely to inhibit glucose oxidation, and that this corresponds to increased myocardial damage following ischemia-reperfusion (I/R) injury.

PMID:40950650 | PMC:PMC12426763 | DOI:10.1096/fba.2025-00187

Am J Transl Res. 2025 Aug 15;17(8):6587-6600. doi: 10.62347/DODM6651. eCollection 2025.

ABSTRACT

OBJECTIVE: This study aimed to explore the mechanisms of Danqi Soft Capsules (DQ) in reducing myocardial ischemia/reperfusion injury (MI/RI) through network pharmacology, molecular docking, and experimental validation.

METHODS: The TCMSP database was used to screen for active ingredients of DQ and their potential targets, and compare them to MI/RI-related targets to construct a "drug-active ingredient-target" network. The protein-protein interaction (PPI) network was constructed using the STRING database; and Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Molecular docking experiments verified the binding affinity between DQ's active ingredients and apoptosis-related target proteins, and cellular experiments validated DQ's anti-apoptotic effects in the H9c2 cardiomyocyte hypoxia/reoxygenation model.

RESULTS: Network pharmacology analysis identified 66 active ingredients and 240 potential targets, of which 105 were related to MI/RI. PPI network analysis screened out 10 core targets. GO and KEGG analyses indicated that these targets were related to the pathways of cell apoptosis. The molecular docking experiment confirmed that the active ingredient had a strong binding affinity with the core target, with the binding affinity between tumor necrosis factor (TNF) and tanshinone IIA being -9.2 kcal/mol, and that between tumor protein (TP) 53 and quercetin being -8.6 kcal/mol. Cellular experimental results showed that the cell apoptosis rate in the DQ-treated group was lower than in the model group, with the protective effect in the high-dose group being slightly better than the low-dose group.

CONCLUSION: This study revealed that DQ alleviates MI/RI by inhibiting cell apoptosis, providing a scientific basis for the clinical application of DQ and offering new directions for drug development.

PMID:40950270 | PMC:PMC12432725 | DOI:10.62347/DODM6651

bioRxiv [Preprint]. 2025 Sep 7:2025.09.02.673841. doi: 10.1101/2025.09.02.673841.

ABSTRACT

Late reperfusion therapy (LRT; ≥ 3 hours post-MI) significantly reduces the risk of ventricular rupture following myocardial infarction (MI), yet the structural and mechanical mechanisms behind this protection remain unclear. We hypothesized that LRT would alter the biomechanical properties of the infarct borderzone and to investigate this, we utilized laser micrometry, planar biaxial testing, and quantitative polarized light imaging (QPLI) to quantify spatial variations in the geometric, mechanical, and structural properties of the left ventricle extracellular matrix (LV ECM) in adult male Sprague-Dawley rats. Rats received permanent occlusion (PO), LRT, or a sham surgery and tissue was collected 1-day post-MI, during the inflammatory phase of healing. LRT generated a larger infarct borderzone (LRT: 31.5 ± 7.6 mm 2 ; PO: 22.5 ± 4.2 mm 2 ; p < 0.05) in comparison to PO. Infarct core and borderzone stiffness was reduced post-MI, and LRT samples exhibited smoother, more consistent stiffness gradients between infarct core and remote regions than PO samples. In general, infarcted LV ECM from were thicker and more spatially variable than sham samples, but less stiff. Additionally, dynamic QPLI revealed decreased collagen fiber alignment in infarct cores relative to borders, though this did not differ between PO and LRT groups. Complementary second harmonic generation imaging revealed more gradual, consistent transitions in collagen fiber alignment throughout LV ECMs subjected to LRT, although this was limited to one sample from each group. Ultimately, these results further justify LRT and may inform future therapeutic strategies aimed at spatially modulating post-MI tissue mechanics to improve patient outcomes.

PMID:40950054 | PMC:PMC12424736 | DOI:10.1101/2025.09.02.673841

World J Cardiol. 2025 Aug 26;17(8):107437. doi: 10.4330/wjc.v17.i8.107437.

ABSTRACT

Mesenchymal stem cells (MSCs) possess unique properties such as immunomodulation, paracrine actions, multilineage differentiation, and self-renewal. Therefore, MSC-based cell therapy is an innovative approach to treating various degenerative illnesses, including cardiovascular diseases. However, several challenges, including low transplant survival rates, low migration to the ischemic myocardium, and poor tissue retention, restrict the application of MSCs in clinical settings. These undesirable cell therapy outcomes mainly originated due to the overproduction of reactive oxygen species (ROS) in the injured heart. MSCs' stress-coping capacity can be enhanced by preconditioning them under conditions similar to the microenvironment of wounded tissues. Hydrogen peroxide (H2O2) is a ROS that has been shown to activate protective cellular mechanisms such as survival, proliferation, migration, paracrine effects, and differentiation at sublethal doses. These processes are induced via phosphatidylinositol 3-kinase/protein kinase B, p38 mitogen-activated protein kinases, c-Jun N-terminal kinase, Janus kinase/signal transducer and activator of the transcription, Notch1, and Wnt signaling pathways. H2O2 preconditioning could lead to many clinical benefits, including ischemic injury reduction, enhanced survival of cellular transplants, and tissue regeneration. In this review, we present an overview of stem cell preconditioning methods and the biological functions activated by H2O2 preconditioning. Furthermore, this review explores the molecular mechanisms underlying the protective cellular functions stimulated under H2O2 preconditioning.

PMID:40949936 | PMC:PMC12426982 | DOI:10.4330/wjc.v17.i8.107437