Basic Research in Cardiology最新文献

{"title":"Melatonin and mitochondrial protection in cardiac ischemia-reperfusion injury: mechanisms, evidence and translational perspectives.","authors":"Gaia Pedriali, Sara Leo, Margherita Tiezzi, Elena Nicoletta Colarusso, Giampaolo Morciano, Elena Tremoli, Paolo Pinton","doi":"10.1007/s00395-026-01162-z","DOIUrl":"10.1007/s00395-026-01162-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"153-185"},"PeriodicalIF":8.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12999662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remote ischemic conditioning protects against anthracycline cardiotoxicity without impairing its antitumor activity.","authors":"Anabel Díaz-Guerra, Agustín Clemente-Moragón, Ángela Pollán, Lucía López-Palomar, Laura Cádiz, Borja Ibáñez","doi":"10.1007/s00395-026-01160-1","DOIUrl":"10.1007/s00395-026-01160-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"211-225"},"PeriodicalIF":8.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amyloid beta 42 disrupts cardiac function in Alzheimer's disease mice via SLC31A1 upregulation-mediated cuproptosis.","authors":"Wenjun Xiong, Zikang Luo, Hong Wang, Qiaozhu Su, Haitao Wang, Jiangping Xu, Wenhua Zheng","doi":"10.1007/s00395-026-01163-y","DOIUrl":"10.1007/s00395-026-01163-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"285-299"},"PeriodicalIF":8.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological reactivation of autophagic flux by natural compounds or synthetic cell-permeable peptide prevents doxorubicin-induced cardiomyopathy.","authors":"Leonardo Schirone,Daniele Vecchio,Valentina Valenti,Vittorio Picchio,Sonia Schiavon,Luca D'Ambrosio,Flavio di Nonno,Selenia Miglietta,Michela Relucenti,Luca Madaro,Silvia Palmerio,Claudia Cozzolino,Margherita Litterio,Gianmarco Sarto,Beatrice Simeone,Nicola Moro,Shazia Tahir,Tania Zaglia,Giuseppe Biondi Zoccai,Elena De Falco,Vincenzo Petrozza,Ernesto Greco,Giacomo Frati,Maurizio Forte,Sebastiano Sciarretta","doi":"10.1007/s00395-026-01174-9","DOIUrl":"https://doi.org/10.1007/s00395-026-01174-9","url":null,"abstract":"Therapeutic strategies to limit doxorubicin (DOX)-induced cardiomyopathy are still limited due to incomplete characterization of the underlying molecular mechanisms. The exogenous activation of autophagy was reported to exert cardioprotective effects in preclinical models of cardiovascular diseases. We tested whether restoration of autophagy by different pharmacological approaches can reduce DOX-induced cardiomyopathy. A validated preclinical murine model of DOX-induced cardiotoxicity (final cumulative dose of 15 mg/kg) was used to test the cardiac effects of both natural (trehalose and spermidine) and synthetic (Tat-Beclin 1 D11) activators of autophagy. Cardiac function was evaluated by echocardiographic analyses. We performed histological analyses (Masson trichrome staining, TUNEL assay) to investigate fibrosis and apoptosis. Biomolecular analyses, confocal and transmission electron microscopy were used to assess levels of autophagy, autophagic flux, mitophagy and mitochondrial alterations. We also evaluated the effects of autophagy activators in a validated syngeneic model with subcutaneous injection of breast cancer cells treated with DOX. We found that DOX-induced cardiotoxicity is associated with impaired autophagic flux (accumulation of LC3-II and p62). Reactivation of autophagic flux by trehalose or spermidine rescues cardiac function and cardiomyocyte survival in mice treated with DOX, along with an overall amelioration of mitochondrial health and mitophagy. Selective reactivation of autophagy by Tat-Beclin 1 D11 also recapitulates the protective effects exerted by trehalose and spermidine. Autophagy activators preserve cardiac function without affecting the antineoplastic effects of DOX in mice with cancer. Boosting autophagic flux is a suitable therapeutic approach to prevent cardiotoxicity induced by anthracyclines.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"21 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147536289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A high-fat diet nutritional intervention reprograms cardiac metabolism and improves systolic function in a pig model of heart failure with reduced ejection fraction.","authors":"Carlos Galán-Arriola,Daniel Pérez-Camargo,Alessia Ferrarini,Annalaura Mastrangelo,María Isabel Higuero-Verdejo,Gonzalo Javier López-Martín,Ana Devesa,Rocío Villena Gutiérrez,Miguel Fernández-Tocino,Anabel Díaz-Guerra,Lourdes Montero-Cruces,Manuel Carnero,Rodrigo Fernández-Jiménez,Valentin Fuster,Javier Sánchez-González,Borja Ibáñez","doi":"10.1007/s00395-026-01171-y","DOIUrl":"https://doi.org/10.1007/s00395-026-01171-y","url":null,"abstract":"Most forms of heart failure are characterized by a metabolic switch from the use of fatty acids to glucose as the main fuel source for ATP generation in the myocardium. Whether metabolic reprogramming is a therapeutic target remains controversial. In this study, heart failure with reduced ejection fraction (HFrEF) and metabolic switch (i.e., increased myocardial glucose uptake) was induced in pigs by generating viable dysfunctional myocardium secondary to progressive coronary artery stenosis. Pigs (n = 19) were then randomized to a high-fat diet (HFD, chow diet supplemented with 20% lard) or control diet (no supplementation) for two months. Pre- and post-nutritional treatment contrast-enhanced cardiac magnetic resonance (CMR) and 18FDG-PET/CT studies were performed. Hearts were then harvested for further analysis. LVEF significantly improved in pigs receiving the 2-month HFD (38% [33, 43] to 54% [47, 62], p = 0.036) but remained unchanged in control-diet pigs (36% [35, 45] to 41% [38, 43], p = 0.24). HFD-fed pigs had a smaller extent of fibrosis after the dietary intervention (late gadolinium enhancement 0.45% LV [0.17, 1.67] vs 6.23 [5.54, 9.57], p = 0.0047). On 18FDG-PET, a reversion of the metabolic reprogramming in the LAD-dysfunctional myocardium was observed only in HFD-fed pigs (0.46 counts [0.21, 0.65] vs 1.80 [1.53, 2.83], p = 0.016). Transmission electron microscopy of explanted hearts revealed less fragmented mitochondrial and a lower lipid droplet density in cardiomyocytes from HFD-fed pigs (38 per 10 µm3 [34, 50] vs 96 [78, 124], p = 0.022), and this was accompanied by increased expression of genes involved in fatty acid metabolism and downregulation of genes encoding glucose import proteins. In conclusion, in a large animal model of HFrEF secondary to myocardial dysfunction with a metabolic switch, a nutritional intervention based on HFD feeding was associated with a cardiac metabolic restoration of fatty acid substrate use, restoration of cardiomyocyte lipid trafficking and significantly improved systolic function.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"61 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATP5A1 succinylation as a key driver for the transition of myocardial ischemia to development of heart failure.","authors":"Lujing Jiang, Shanshan Chen, Senlin Li, Cui Liu, Changmin Xie, Yu He, Yani Shi, Fang Liu, Chengyang Lai, Qingfeng Xie, Peiqing Liu, Wenwei Luo, Shilong Zhong, Zhuoming Li","doi":"10.1007/s00395-026-01172-x","DOIUrl":"https://doi.org/10.1007/s00395-026-01172-x","url":null,"abstract":"<p><p>Myocardial ischemia is the common etiology of heart failure (HF). However, the precise molecular mechanisms that govern the ischemic myocardium into HF remain poorly defined. Selective accumulation of succinate is a hallmark of ischemia. Succinate is a predominant regulator of protein succinylation modification. The present study unravels the novel role of succinate in ischemia-induced HF via succinylation. A clinical cohort study that was performed on 1554 Chinese patients with coronary artery disease (CAD) indicated that serum succinate levels were positively correlated with the increase of HF biomarker, decrease of left ventricular ejection fraction (LVEF), incidence of HF, and risk of death. In cardiomyocytes deprived of oxygen and glucose (OGD) and in mice subjected to ligation of the left anterior descending coronary artery (LAD), succinate levels and global protein succinylation were elevated. Succinylation proteomic analysis identified the α-subunit of mitochondrial ATP synthase (ATP5A1) as an important succinylated protein, and K531 was identified as the functional succinylation site. Ablation of succinylation by the ATP5A1-K531R mutant ameliorated OGD-induced cardiomyocyte death, mitochondrial dysfunction and energy metabolic dysfunction. K531R delivered by cardiac-specific adeno-associated virus (AAV9) achieved short-term cardioprotective effects against ischemic injury, and exerted prolonged protective effects against HF development. Sirtuin 5 was confirmed as a desuccinylase of ATP5A1, whereas carnitine palmitoyltransferase 1A (CPT1A) was recognized as a trans-succinylase. Mechanistically, succinylation of ATP5A1-K531 impeded the assembly of ATP synthase and impaired its activity. Elevated succinate potentially serves as a risk predictor of HF. Targeting desuccinylation of ATP5A1-K531 might be a promising therapeutic strategy.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term blockade of E-prostanoid 3 receptor mitigates necroinflammation and ameliorates ischemia/reperfusion- and doxorubicin-induced acute myocardial injury.","authors":"Dong He,Yequn Chen,Jiahui Ge,Jinwei Guo,Zhen Wang,Gang Yu,Shiwan Wu,Jing Leng,Bin Wang,Shunyu Pang,Xijian Chen,Yineng Xu,Cheng Peng,Jianye Yang,Shijun Liu,Anhong Cai,Zhengpeng Zeng,Xinya Shi,Siyi Ling,Yukuan Chen,Yingbi Zhou,Bin Liu","doi":"10.1007/s00395-026-01173-w","DOIUrl":"https://doi.org/10.1007/s00395-026-01173-w","url":null,"abstract":"E-prostanoid 3 receptor (EP3) plays an important role in maintaining normal heart growth and development, and its activation may drive acute inflammation and influence intracellular Ca2+ level. The effects of targeting EP3 on myocardial injury have been very controversial. We aimed to elucidate roles of EP3 in both innate immune cells and cardiomyocytes during the acute phase of acute myocardial injury. Wild-type, global Ep3 knockout (Ep3-/-), myeloid conditional Ep3-deficient (Ep3F/F;Lyz2Cre) and tamoxifen-induced cardiomyocyte-specific Ep3 knockout (Ep3F/F;Myh6MerCreMer) mice were subjected to regional ischemia/reperfusion (I/R) or acute doxorubicin (DOX) treatment. Inflammation, prostaglandin production, and damage-associated molecular pattern (DAMP) release were induced in acute myocardial injury in mice and patients. Injury caused by I/R or DOX was substantially ameliorated in EP3 antagonist-treated wild-types, but not in their Ep3-/- counterparts. I/R injury was alleviated in Ep3F/F;Lyz2Cre rodents and Ep3F/F;Myh6MerCreMer mice at 1 week after the administration of tamoxifen, but exacerbated in the latter at 8 weeks. Germline Ep3-/- hearts were predisposed to abnormalities. Antagonism or myeloid deficiency of EP3 ameliorated I/R injury by suppressing inflammation and regulating necrosis pathways, constituting an auto-amplification loop of necroinflammation. EP3 disruption in cardiomyocytes prevented the agonist-induced increase of diastolic Ca2+ level. Short-term EP3 abrogation in cardiomyocytes also reduced local and systemic inflammation after I/R. Collectively, long-term EP3 abrogation predisposes hearts to abnormalities and is detrimental; however, its deficiency in myeloid cells or transient deletion in cardiomyocytes convergently mitigates necroinflammation and alleviates acute myocardial injury, indicating short-term EP3 blockade is a potentially promising therapeutic strategy for such diseases.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"33 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights in ischemia/reperfusion injury and cardioprotection: neglected and emerging pathways and therapeutic targets for a personalized therapy.","authors":"Pasquale Pagliaro,C Penna,S Femminò,F G P Welt","doi":"10.1007/s00395-026-01167-8","DOIUrl":"https://doi.org/10.1007/s00395-026-01167-8","url":null,"abstract":"Despite extensive preclinical research identifying molecular targets and cardioprotective strategies, translation into effective clinical therapies remains challenging. Cardioprotection aims to mitigate ischemia/reperfusion injury (IRI) by modulating molecular pathways, such as the Reperfusion Injury Salvage Kinase (RISK) and Survivor Activating Factor Enhancement (SAFE) pathways, as well as autophagy, inflammation, and regulated cell death, to preserve myocardial function. However, a major limitation lies in the robustness of preclinical evidence. Many experimental studies rely on simplified models that fail to reproduce the complexity of human cardiac pathophysiology, resulting in inconsistent and poorly reproducible cardioprotective effects. It is likely that RISK-SAFE pathways represent an oversimplified framework. Moreover, most experimental approaches are cardiomyocyte-centered, overlooking the critical role of the vessels in IRI. Clinical translation is further compromised by patient-related factors, including comorbidities (e.g., diabetes, hypertension), concomitant medications, and heterogeneity in reperfusion protocols, all of which attenuate cardioprotective efficacy. Additional variables, such as timing of intervention and species differences, further contribute to translational failure. Emerging approaches include pharmacological therapies (e.g., SGLT2 inhibitors, PARP inhibitors, necroptosis and ferroptosis blockers, NLRP3-targeting compounds), cell- and organelle-based strategies (e.g., mitochondrial transplantation, extracellular vesicles, non-coding RNAs), and mechanical/device-based interventions (e.g., left ventricular unloading, ischemic conditioning, controlled reperfusion, selective intracoronary hypothermia). Future research should emphasize multi-target interventions, optimized timing and delivery, and advanced tools, such as nanocarriers, gene therapy, computational modeling, and adaptive clinical trials. Strengthening the robustness of preclinical models, including human ex vivo cardiac systems, remains essential to bridge the translational gap and improve the clinical success of cardioprotective therapies.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"8 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARKIN overexpression confers cardioprotection via suppressing the mtDNA-cGAS-STING axis in myocardial ischemia/reperfusion injury.","authors":"Yujing Li,Yuhan Wang,Hao Zhang,Pengfei Xu,Xiaosu Yuan,Hailong Yuan,Chaofan Yang,Yanan Zhou,Jianghua Shen,Heng Du,Zeyu Gao,Jingyi Zang,Siwen Liang,Jing Qu,Moshi Song","doi":"10.1007/s00395-026-01169-6","DOIUrl":"https://doi.org/10.1007/s00395-026-01169-6","url":null,"abstract":"Myocardial ischemia/reperfusion (I/R) injury is exacerbated by inflammation, yet the upstream triggers of this cascade and their amenability to therapeutic intervention remain unclear. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a driver of sterile inflammation in I/R injury, but whether its activation can be suppressed via enhanced mitochondrial quality control has not been explored. We hypothesized that augmenting PARKIN-mediated mitophagy would limit cGAS-STING activation and attenuate I/R injury by clearing damaged mitochondria and preventing the release of its agonist, mitochondrial DNA (mtDNA). Cardiomyocyte-specific PARKIN overexpression in mice was well tolerated at baseline and conferred cardioprotection following I/R injury, attenuating adverse remodeling and preserving cardiac function. Mechanistically, PARKIN overexpression enhanced mitophagy, which limited cytosolic mtDNA accumulation, thereby inhibiting cGAS-STING activation and its downstream inflammatory response. The therapeutic potential of this pathway was further supported by lentiviral PARKIN delivery in wild-type mouse hearts, which also improved cardiac outcomes following I/R injury. Taken together, our findings delineate a PARKIN-mtDNA-cGAS-STING axis as a regulatory mechanism of I/R injury and support PARKIN augmentation as a potential therapeutic strategy.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"17 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time course of early and delayed myocardial protection induced by vagal nerve stimulation preconditioning.","authors":"Verena B Franco-Riveros,Jazmín Kelly,Timoteo Marchini,Virginia Pérez,Eduardo A Bernatené,Elizabeth Robello,Mónica Galleano,Martín Donato,Pablo Evelson,Ricardo J Gelpi,Bruno Buchholz","doi":"10.1007/s00395-026-01165-w","DOIUrl":"https://doi.org/10.1007/s00395-026-01165-w","url":null,"abstract":"We previously reported that pre-ischemic vagus nerve stimulation (VNS) protects against myocardial ischemia, resembling classical ischemic preconditioning (cPC). This study investigates the time course and mechanisms underlying VNS-induced cardioprotection. Male FVB/N mice (3-5 months) underwent 30 min regional myocardial ischemia followed by 120 min reperfusion (IR). Ten-minute right-sided cervical VNS was delivered at defined intervals before ischemia to assess early and delayed protective windows. Risk area (RA) and infarct size (IS) were quantified using Evans Blue/tetrazolium staining. Myocardial phosphorylation of protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), inducible nitric oxide synthase (iNOS), and mitochondrial respiration were evaluated. IR controls exhibited an IS of 57 ± 7% of the RA. VNS elicited a biphasic cardioprotective response. Early protection was observed when ischemia occurred 5 min, 3 h, or 6 h after VNS, with IS reduced to 44 ± 8%, 34 ± 7%, and 36 ± 9%, respectively (p ≤ 0.0001 vs. IR). This phase depended on muscarinic acetylcholine receptor (mAChR) activation, involved Akt/GSK-3β/NOS signaling, and was associated with preserved mitochondrial respiration. The protective effect was abolished by atropine, NG-nitro-L-arginine methyl ester (L-NAME), or the mitoKATP channel blocker 5-hydroxydecanoate (5HD). Delayed protection emerged 72 h after VNS, reducing IS to 42 ± 7% (p = 0.0001 vs. IR). This phase was independent of mitochondrial respiration preservation and required mAChR and iNOS signaling, as it was abolished by atropine, L-NAME, or the selective iNOS inhibitor 1400W, but not by 5HD. These findings identify pre-ischemic VNS as a biphasic cardioprotective strategy with distinct phase-specific mechanisms, highlighting its potential therapeutic relevance in limiting IR injury.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"263 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}