Basic Research in Cardiology最新文献

Cardiac ischemia-reperfusion injury (IRI) leads to significant mitochondrial impairment, which contributes to cell death and hampers myocardial recovery. During IRI, mitochondria are subjected to oxidative stress, calcium overload, and altered dynamics, resulting in the opening of the mitochondrial permeability transition pore (mPTP), release of cytochrome c, and activation of apoptotic pathways. Melatonin, a pleiotropic indoleamine produced by the pineal gland and other tissues, has cardioprotective effects through both direct antioxidant activity and receptor-mediated mechanisms. This review explores melatonin's role in maintaining mitochondrial integrity under IRI conditions. Melatonin counteracts oxidative damage by neutralizing reactive oxygen species, stabilizing mitochondrial membrane potential, and preventing mPTP opening, thereby reducing activation of cell death pathways. It also supports mitochondrial biogenesis and dynamics, contributing to energy balance and reduced oxidative burden. In addition, melatonin regulates mitophagy, ensuring mitochondrial quality control and preventing excessive degradation, which collectively contributes to restoring mitochondrial function and cellular metabolism. In rodent preclinical models, melatonin administration before ischemia, during ischemia, or at reperfusion has consistently reduced infarct size and improved cardiac function. While these preclinical findings are encouraging, studies on rabbits or pigs and clinical studies have not consistently replicated these benefits. The variability in outcomes may be attributed to differences in study design, timing and method of melatonin administration, and types of endpoints measured. Comorbidities, risk factors, and comedications further influence mitochondrial biology and melatonin's efficacy in cardiac IRI. A dedicated comparative analysis evaluates melatonin against established and emerging cardioprotective approaches targeting mitochondria, underscoring its potential for combination therapies.

Anthracyclines remain a cornerstone of treatment for many cancer types; however, their cardiotoxic potential leads to cardiac dysfunction in a substantial proportion of patients, ultimately compromising long-term quality of life. Few strategies have proven effective in preventing anthracycline-induced cardiotoxicity (AIC). Among them, remote ischemic conditioning (RIC) has emerged as one of the most promising, having shown robust cardioprotective potential in preclinical studies and currently being evaluated in clinical trials. However, it remains unclear whether this intervention, while protecting the heart, could also inadvertently protect tumors from the cytotoxic effects of anthracyclines, thereby reducing their antitumor efficacy. In this study, we investigated whether RIC protects against AIC in a tumor-bearing mouse model, allowing simultaneous assessment of both cardiac and tumoral responses. Cutaneous tumors were induced in CD1 mice using a DMBA/TPA protocol, followed by five weekly intraperitoneal injections of doxorubicin (5 mg/kg). Mice bearing tumors were randomized to receive doxorubicin alone or in combination with weekly RIC (three cycles of 5 min hindlimb ischemia/reperfusion). Longitudinal echocardiography was used to assess cardiac function, while tumor growth, survival, and body weight were monitored throughout the protocol. Doxorubicin treatment reduced overall survival, inhibited tumor growth, and induced left ventricular systolic dysfunction and cardiac atrophy compared with untreated controls. RIC preserved left ventricular ejection fraction, partially attenuated early left ventricular atrophy, and showed a trend towards improved survival, without attenuating the antitumor efficacy of doxorubicin, as tumor suppression remained comparable between treatment groups. These findings demonstrate that RIC preserves cardiac systolic function during anthracycline chemotherapy in tumor-bearing mice without impairing the antitumor efficacy of the drug. The results support RIC as a simple, safe, and low-cost non-pharmacological strategy to mitigate AIC with potential translational relevance for oncology patients.

Background Alzheimer's disease (AD) is a complex systemic disorder that extends beyond the central nervous system, exerting pathological effects on the heart. Epidemiological studies have consistently shown that individuals with AD often exhibit impaired cardiac function. While amyloid-beta (Aβ) is a key pathological hallmark of AD, primarily known for forming oligomers and fibrils in the brain, emerging evidence suggests that Aβ also exerts detrimental effects on the myocardium. Despite these observations, the precise mechanisms through which AD contributes to the onset or progression of heart failure (HF) remain poorly understood. This study aims to elucidate the underlying links between AD and HF, with a specific focus on the pathogenic role of Aβ in promoting cardiac dysfunction within experimental models of AD. Methods Cardiomyocytes and 3 × Tg-AD mouse models were used to investigate Aβ-induced cardiotoxicity and to determine the mode of myocardial cell death. We assessed cell viability, intracellular copper levels, and markers of cuproptosis. Mitochondrial oxidative respiration, ATP production, and reactive oxygen species (ROS) levels were also evaluated. Myocardial pathology and cuproptosis-related proteins were detected by histochemistry and immunoblotting. Results In 3 × Tg-AD mice, elevated cardiac Aβ paralleled cardiac dysfunction, promoted cuproptosis in cardiomyocytes, and this effect was counteracted by the copper chelator TTM which inhibited myocardial copper uptake and protected cardiac function. Building on this in vivo observation, we further investigated the mechanism in vitro and found that Aβ upregulated the copper importer SLC31A1 in vitro. Furthermore, Aβ1-42 acted synergistically with CuCl₂ or elesclomol-CuCl₂ to exacerbate cardiomyocyte death. This synergy increased intracellular copper accumulation, triggered Fe-S cluster protein loss, and promoted DLAT oligomerization-hallmarks of cuproptosis. These cuproptosis-associated changes suppressed mitochondrial oxidative respiration, decreased ATP synthesis, and elevated ROS levels. Importantly, interference with SLC31A1 expression in vivo and in vitro partially inhibited cuproptosis and protected mitochondrial or cardiac function. Conclusion Aβ1-42 disrupts copper homeostasis by upregulating SLC31A1, thereby exacerbating myocardial cuproptosis and impairing cardiac function in AD. This novel mechanism highlights SLC31A1-mediated cuproptosis as a potential therapeutic target for preserving cardiac health in AD.

Angiogenesis is an important repair mechanism for myocardial infarction. Neuroligin-3 (NLGN3) can promote angiogenesis by activating Gαi1/3-Akt signaling following ischemic brain injury. This study investigated the role of NLGN3 in myocardial infarction (MI). On the 7th day after MI, the plasma level of NLGN3 in patients was significantly higher than in the control group. A mouse model of MI also showed significantly increased expression of NLGN3 in heart tissue. Single-nucleus transcriptome analysis revealed that NLGN3 was located predominantly in cardiac fibroblasts and endothelial cells (ECs). Endothelial-specific knockdown of NLGN3, or inhibition of NLGN3 using ADAM10i, significantly increased the ischemic area, reduced angiogenesis, and worsened cardiac function. Co-immunoprecipitation (Co-IP) experiments showed that NLGN3 interacted with Gαi1/3. The Gαi1/3 knockout (Gαi1/3-KO) mouse model of MI showed an increased ischemic area, decreased angiogenesis, and impaired cardiac function. Mechanistic studies showed that the NLGN3-Gαi1/3 signaling pathway exerts cardioprotective effects by promoting EC proliferation and tube formation through the PI3K-Akt-mTOR pathway. Silencing of Gαi1/3 largely eliminated the ability of NLGN3-promoting cardiac ECs to proliferate and form tubes. Our findings suggest the endothelial NLGN3-Gαi1/3 signaling pathway promotes angiogenesis and reduces the ischemic area following MI, which is critical for maintaining cardiac function and repairing tissues. Targeting of the NLGN3-Gαi1/3 signaling pathway may have clinical therapeutic potential in protecting the heart from ischemic injury.