Journal of molecular and cellular cardiology plus最新文献

{"title":"Coxsackie and adenovirus receptor is a novel regulator of inflammatory response in endotoxin-induced failing heart.","authors":"Reo Matsumura ,&nbsp;Mototsugu Nishii ,&nbsp;Haruya Usuku ,&nbsp;Masahiro Nakayama ,&nbsp;Masaki Hachisuka ,&nbsp;Naho Misawa ,&nbsp;Ryo Saji ,&nbsp;Fumihiro Ogawa ,&nbsp;Alan Valaperti ,&nbsp;Yoshihiro Ishikawa ,&nbsp;Ichiro Takeuchi","doi":"10.1016/j.jmccpl.2025.100496","DOIUrl":"10.1016/j.jmccpl.2025.100496","url":null,"abstract":"<div><div>The regulatory mechanisms for inflammatory response in the heart to endotoxin, which causes severe cardiac dysfunction, are not fully understood. We hypothesized the involvement of coxsackie and adenovirus receptor (CXADR), which can promote tissue inflammation by potentiating cell-cell adhesion, independent of viral infection, and examined the role of CXADR in endotoxin-induced cardiac dysfunction and its mechanism using an experimental mouse model. Conditional whole-body and endothelium-specific CXADR knockout (W-KO and <em>E</em>-KO, respectively) mice were generated using the Cre-loxP system and administered lipopolysaccharide (LPS) or vehicle alone, like wild-type (WT) mice. Cardiac CXADR increased 12 h after LPS challenge in WT mice, along with improved cardiac dysfunction and reduced cardiac expression of interleukin (IL)-6 and IL-1β. Moreover, W-KO in adult mice worsened cardiac dysfunction and increased expression of these cytokines. Meanwhile, <em>E</em>-KO exhibited the opposite effects, concomitantly reducing myocardial inflammation. Bulk RNA sequencing analysis identified an enriched IL-17 A signaling pathway capable of inducing IL-6 and IL-1β expression in the heart 12 h after LPS challenge. In this heart, <em>E</em>-KO attenuated phosphorylation of p38 but not of upstream mitogen-activated protein kinase kinase (MKK)3/6. Conversely, W-KO augmented phosphorylation of p38, MKK3/6, and NF-κB/p65, which are key drivers of the IL-17 A signaling. Our study is the first to demonstrate that increased CXADR expression plays a dual role as both a pro-inflammatory mediator and an anti-inflammatory protector in endotoxin-induced cardiac dysfunction, possibly by positively or negatively regulating p38 activation depending on its cellular origin. Targeted manipulation of CXADR expression may provide clinical benefits.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100496"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-driven cytokine immunomodulation ameliorates cardiac function and suppresses fibrosis","authors":"Laris Achlaug ,&nbsp;Lama Awwad ,&nbsp;Irina Langier Goncalves ,&nbsp;Sharon Aviram ,&nbsp;Ariella Glasner ,&nbsp;Ami Aronheim","doi":"10.1016/j.jmccpl.2025.100493","DOIUrl":"10.1016/j.jmccpl.2025.100493","url":null,"abstract":"<div><div>Heart failure remains a leading cause of morbidity and mortality worldwide, with limited progress in the development of novel therapies. It has been demonstrated that tumor growth improves cardiac function and reduces myocardial fibrosis in mouse models of heart failure. It is clear that cancer cell implantation is not a possible therapeutic strategy for heart failure. Therefore, we further studied the underlying mechanism involved, with the objective of demonstrating its broad therapeutic applicability. We show that a single intravenous injection of serum from tumor-bearing mice rapidly augments left-ventricular fractional shortening and suppresses fibrosis in the heart, diaphragm, and skeletal muscles. Cytokine profiling identified IFNγ and TNFα as essential mediators secreted downstream of natural killer (NK) cell activation. Purified recombinant IFNγ and TNFα mimic the serum effect, polarizing cardiac and skeletal macrophages toward an anti-inflammatory, reparative state. We further show that macrophage depletion abrogates the observed beneficial effect, confirming their critical role. Our findings define a novel NK cell–macrophage cytokine axis that reverses cardiac dysfunction and fibrosis in pressure-overload (transverse aortic constriction) and ATF3-transgenic heart failure models. Together, these findings define a novel host-tumor microenvironment response through cytokine secretion, which leads to cardiac repair and dissolution of fibrosis. This work presents a novel therapeutic strategy for harnessing innate immune cells in the treatment of heart failure and fibrotic disease.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100493"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FABP3 and FABP4 promote lipid peroxidation injury during static cold storage of donor heart: Insights from multi-omics and therapeutic targeting","authors":"Yu Feng ,&nbsp;Yongbu Peng ,&nbsp;Jincheng Hou ,&nbsp;Zihao Wang ,&nbsp;Junlin Lai ,&nbsp;Tixiusi Xiong ,&nbsp;Jiawei Shi ,&nbsp;Yixuan Wang ,&nbsp;Wai Yen Yim ,&nbsp;Yuqi Chen ,&nbsp;Nianguo Dong","doi":"10.1016/j.jmccpl.2025.100497","DOIUrl":"10.1016/j.jmccpl.2025.100497","url":null,"abstract":"<div><h3>Objectives</h3><div>To clarify the mechanism of myocardial injury associated with lipid peroxidation and the role of fatty acid binding proteins FABP3/4 during Static cold storage (SCS) of donor hearts.</div></div><div><h3>Methods</h3><div>Multi-omics analysis included mouse myocardial metabolomics and transcriptomics, proteomics of cardiac preservation solution in SCS injury. Lipid peroxidation was detected by malondialdehyde, transmission electron microscopy (TEM), and fluorescent probes. Lipid peroxidation antagonist MitoQ was examined by TEM. FABP3/4 were analyzed by combining the proteomic data of first perfusion serum from human donor hearts with those of mouse myocardial SCS solution. Overexpressing FABP3/4 were evaluated by detecting ROS and apoptosis via flow cytometry. snRNA-seq revealed the cellular landscape of SCS injury in pig cardiomyocytes.</div></div><div><h3>Results</h3><div>Multi-omics analysis of the SCS injury model revealed significant changes in lipid metabolism. Disturbed lipid metabolism and peroxidation were demonstrated in mouse SCS injury model and cell model. MitoQ attenuated lipid peroxidation and antagonized cardiac SCS injury. FABP3/4 were released during SCS and promoted injury in cardiomyocytes. In SCS solution, FABP3/4 expression were improved in both short-term and long-term SCS. In myocardial tissue, FABP3 expression decreased during short-term SCS and then gradually increased after long-term SCS. FABP4 expression were first upregulated and then decreased, remaining stable during long-term SCS. Pig cardiomyocytes showed low FABP3 and high FABP4 expression during short-term SCS.</div></div><div><h3>Conclusion</h3><div>Disturbed lipid metabolism and peroxidation occur during SCS of hearts. FABP3/4 promote lipid uptake and aggravate SCS damage. FABP3/4 should be further investigated as potential therapeutic targets for SCS injury during heart transplantation.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100497"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145571637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signaling pathway alterations in hearts of a porcine model harboring a β-myosin heavy chain (MYH7-R403Q) gene variant","authors":"Chad M. Warren ,&nbsp;David M. Ryba ,&nbsp;Gail E. Geist ,&nbsp;Aileen Castro Coronado ,&nbsp;Beata M. Wolska ,&nbsp;Paul H. Goldspink ,&nbsp;R. John Solaro","doi":"10.1016/j.jmccpl.2025.100495","DOIUrl":"10.1016/j.jmccpl.2025.100495","url":null,"abstract":"<div><div>The disease-causing myosin variant (MYH7-403Q) is linked to hypertrophic cardiomyopathy (HCM). We carried out a research study of signaling pathways in heart samples from control wild-type (WT) GE Yucatán mini-pigs and their littermates harboring the gene variant, MYH7-R403Q. Our approach permits the determination of adverse signaling pathways involved in different regions of a translationally relevant heart without the effects of intervention. We examined the left ventricular free wall (LV), endocardium (EN), and coronary arteries (CA) from 5 transgenic and 5 wild-type mini-pig littermates to determine alterations in global phosphorylation and protein abundance. Digested peptides from 6 to 7 months old mixed-sex mini-pigs were isobarically labeled; 95 % were phospho-enriched, and 5 % were used as the unmodified (total) fraction. The phospho-enriched and unmodified fractions were injected into an Orbitrap Fusion Lumos and analyzed using PEAKS Studio and Ingenuity Pathway Analysis. Surprisingly, we found no significant changes in the phospho-peptide and unmodified protein abundances in CA. Compared to WT, both LV and EN samples displayed minor changes in phosphorylation and significant changes in unmodified proteins. Bioinformatic analysis revealed that pathways associated with mechano-signaling between cardiomyocytes and the extracellular matrix and inflammation were altered in LV and EN samples. In addition, EN samples had larger differences in pathways related to metabolic dysfunction compared to LV. Our findings provide a translational understanding of signaling pathways altered in the MYH7-R403Q gene variant.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100495"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145467015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rab10 plays a protective role in the development of pathological cardiac hypertrophy","authors":"Fang Xu ,&nbsp;Min Wu ,&nbsp;Yihan Wang ,&nbsp;Haiyan Luo ,&nbsp;Xiaobo Gao ,&nbsp;Song Lai ,&nbsp;Cailing Lu","doi":"10.1016/j.jmccpl.2025.100494","DOIUrl":"10.1016/j.jmccpl.2025.100494","url":null,"abstract":"<div><div>Prolonged cardiac hypertrophy is a main risk factor for heart failure (HF). During cardiac hypertrophy remodelling, there is an increase in protein synthesis, as well as the trafficking and localization of proteins to their functional sites. Rab GTPases, which are key regulators of vesicular formation, movement, and fusion, play a crucial role in these processes. In this study, we identified Rab10, a small GTPase belonging to the Rab family, as a novel regulator to inhibit cardiac hypertrophy. Cardiomyocyte hypertrophy was induced by Ang II or pressure overload in primary neonatal rat cardiomyocytes (NRCMs) or mouse model. We found that Rab10 expression was downregulated in NRCMs or murine hearts after hypertrophic stress. Rab10 overexpression attenuated cardiomyocyte hypertrophy, whereas its silencing exacerbated the phenotype, demonstrating its essential antihypertrophic role <em>in vitro</em>. To determine the <em>in vivo</em> role of Rab10 in the heart, we generated cardiac-specific Rab10-overexpressing transgenic mice (TG). When subjected to Ang II infusion or pressure overload, Rab10 TG mice displayed an improved contractile function and attenuated hypertrophic remodelling. In contrast, AAV9-mediated cardiac-specific knockdown of Rab10 significantly aggravated pressure overload-induced cardiomyocyte hypertrophy. Mechanically, Rab10 suppressed the phosphorylation of ERK1/2 and AKT, thereby attenuating the development cardiac hypertrophy. Additionally, we demonstrated that Rab10 was post-transcriptionally downregulated by miR-199a. In summary, our findings revealed a novel role for Rab10 in pathogenic cardiac hypertrophy and suggest that Rab10 may be a potential therapeutic target for cardiac hypertrophic.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100494"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age, sex, and vessel region affect the vasomotor function and gene expression signature of the aorta in mice","authors":"Lars Saemann ,&nbsp;Lotta Hartrumpf ,&nbsp;Adrian-Iustin Georgevici ,&nbsp;Sabine Pohl ,&nbsp;Anne Großkopf ,&nbsp;Kristin Wächter ,&nbsp;Yuxing Guo ,&nbsp;Andreas Simm ,&nbsp;Gábor Szabó","doi":"10.1016/j.jmccpl.2025.100491","DOIUrl":"10.1016/j.jmccpl.2025.100491","url":null,"abstract":"<div><h3>Introduction</h3><div>Vascular aging is associated with endothelial dysfunction, changes in vascular elasticity or stiffness, and the prevalence of cardiovascular diseases. Aging differs by sex. The effects of age, sex, and vessel region on arterial vasomotor function and gene expression signatures have not been explored yet. Thus, we investigated contraction, relaxation, and endothelial integrity, as well as gene expression, in the proximal and distal segments of the thoracic aorta in 6- and 18-month-old mice.</div></div><div><h3>Materials and methods</h3><div>Male and female C57BL/6J mice at 6 (<em>n</em> = 11/sex) and 18 (<em>n</em> = 12/sex) months of age were used. Segments of the proximal and distal thoracic aorta were mounted in organ bath chambers. We assessed the maximal receptor-independent contractility using potassium chloride (KCl), endothelial integrity using phenylephrine (PE), endothelial-dependent relaxation using acetylcholine (ACh), and endothelial-independent relaxation using sodium nitroprusside (SNP). Using microarrays, we performed transcriptomics on another 6 six mice of every subgroup.</div></div><div><h3>Results</h3><div>Endothelial integrity decreases significantly with age in male mice, but only in the proximal segment. The relaxation to ACh decreases with age in both sexes in the proximal and only in female individuals in the descending segment. In females, endothelial-dependent relaxation is higher than in males, in young age, independent of the segment, and in old age, still in the proximal segment. Endothelial-independent relaxation decreases with age only in the distal segment of female subjects. Genes associated with the electron transport chain, crucial for energy production in mitochondria, are decreased by age. The G-protein coupled receptor -G13 alpha subunit- signaling pathway and proteasome degradation, which are crucial for developing and maintaining endothelial integrity, were reduced in the aorta of old mice. Genes involved in endothelial nitric oxide synthesis were especially downregulated in old male mice.</div></div><div><h3>Conclusion</h3><div>Endothelial integrity and endothelial-dependent relaxation depend on age, sex, and segment of the descending thoracic aorta in mice. Genes associated with endothelial-dependent relaxation, endothelial integrity, and vascular aging change markedly by age, including some sex- and segment-specific differences.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100491"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy","authors":"Jordan S.F. Chan ,&nbsp;Seyed Amirhossein Tabatabaei Dakhili ,&nbsp;Nadeen R. Wu ,&nbsp;Magnus J. Stenlund ,&nbsp;Alexa N. King ,&nbsp;Linyue Dong ,&nbsp;Indiresh A. Mangra-Bala ,&nbsp;Tanin Shafaati ,&nbsp;Sally R. Ferrari ,&nbsp;Amanda A. Greenwell ,&nbsp;Kunyan Yang ,&nbsp;Christina T. Saed ,&nbsp;Farah Eaton ,&nbsp;Keshav Gopal ,&nbsp;Gregory R. Steinberg ,&nbsp;Jason R.B. Dyck ,&nbsp;John R. Ussher","doi":"10.1016/j.jmccpl.2025.100825","DOIUrl":"10.1016/j.jmccpl.2025.100825","url":null,"abstract":"<div><div>The first line therapy for managing type 2 diabetes (T2D), metformin, has been shown to be cardioprotective in humans and several preclinical models of cardiovascular disease. However, there has been limited interrogation into metformin's effects on diastolic function, a hallmark characteristic of diabetic cardiomyopathy (DbCM), which is becoming increasingly prevalent in people with pre- and early-stage T2D. Accordingly, we aimed to determine the effects of metformin on the pathogenesis of DbCM and hypothesized that treatment with metformin would alleviate diastolic dysfunction in mice with T2D. To induce experimental T2D and DbCM, male C57BL/6J mice were fed a high-fat diet for 12.5 weeks, in combination with a single, low-dose injection of streptozotocin (75 mg/kg) at week 4.5. The animals' drinking water was randomized to include either vehicle control or metformin (3.0 g/L) during the final 7.5 weeks. As expected, metformin treatment improved glycemia with a trend towards a reduction in adiposity in mice with T2D. Using ultrasound echocardiography, we observed that metformin improved diastolic function in mice with T2D as reflected by an increase and a decrease in the e′/a′ and E/e′ ratios, respectively. Furthermore, wheat-germ agglutinin staining indicated that treatment with metformin decreased cardiomyocyte hypertrophy in mice with T2D. However, mice with T2D treated with metformin did not exhibit increases in myocardial adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Thus, our findings suggest that metformin has salutary actions against DbCM and its associated diastolic dysfunction, which may be independent of its ability to increase AMPK activity.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100825"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial metabolic remodeling and multi-omics profiling identify plasma biomarkers of myocardial infarction","authors":"Selvam Paramasivan ,&nbsp;Mitchell C. Lock ,&nbsp;Roberto A. Barrero ,&nbsp;Paul C. Mills ,&nbsp;Janna L. Morrison ,&nbsp;Pawel Sadowski","doi":"10.1016/j.jmccpl.2025.100827","DOIUrl":"10.1016/j.jmccpl.2025.100827","url":null,"abstract":"<div><div>Mitochondrial dysfunction is a hallmark of myocardial infarction (MI), yet the molecular mechanisms linking metabolic reprogramming in the ischemic myocardium to systemic biomarker signatures remain incompletely understood. In this study, we employed a data-independent acquisition mass spectrometry (SWATH-MS) strategy integrating multi-omics analysis with upstream regulatory network analysis to investigate mitochondrial energy pathway alterations in a preclinical ovine model of MI. Proteomic profiling of infarcted myocardium revealed a pronounced shift from oxidative phosphorylation to glycolysis, accompanied by coordinated suppression of mitochondrial fatty acid β-oxidation enzymes. This metabolic reprogramming was strongly associated with four upstream master regulators, most notably predicted inhibition and significant transcriptional downregulation of <em>PPARGC1A</em>, a key coactivator of mitochondrial biogenesis and oxidative metabolism, indicating disrupted mitochondrial energy homeostasis and impaired adaptive responses in ischemic cardiomyocytes. Parallel plasma proteomic analysis identified a distinct panel of differentially expressed proteins enriched in pathways related to carbon metabolism, amino acid biosynthesis, and cardiac muscle contraction. Notably, mitochondrial metabolic enzymes such as <em>SUCLG1</em>, <em>MDH2</em>, <em>HADHA</em>, and <em>HADHB</em> were significantly downregulated at both the transcript and protein levels in cardiac tissue, while their protein abundance was markedly increased in plasma post-MI, highlighting their potential as circulating biomarkers of mitochondrial dysfunction. These findings provide mechanistic insight into the energy metabolic remodeling that occurs during myocardial ischemic injury and establish a systems-level framework for linking tissue-specific mitochondrial alterations with accessible plasma biomarkers. This study supports the translational potential of targeting mitochondrial pathways for diagnostic and therapeutic strategies in ischemic heart disease.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100827"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired PGC-1α-pAMPK signaling in postmenopausal women undergoing cardiac surgery and the role of nicotinamide in its reversal: Insights from a murine model","authors":"Mark Robitaille ,&nbsp;Usman Ahmed ,&nbsp;Juan Valencia ,&nbsp;Adnan Khan ,&nbsp;Adil al-Karim Manji ,&nbsp;Elizabeth Russ ,&nbsp;Louis Chu ,&nbsp;Kamal Khabbaz ,&nbsp;Feroze Mahmood ,&nbsp;Robina Matyal","doi":"10.1016/j.jmccpl.2025.100831","DOIUrl":"10.1016/j.jmccpl.2025.100831","url":null,"abstract":"<div><div>Postmenopausal women undergoing cardiac surgery face disproportionately worse outcomes compared with men, a disparity linked to mitochondrial dysfunction following estrogen loss. We investigated sex-specific metabolic responses to cardiac stress in surgical patients and in a murine model of postmenopausal dysfunction, with a focus on proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling and the therapeutic potential of nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD⁺). In a prospective cohort of 102 patients (51 men, 51 women) undergoing cardiac surgery with cardiopulmonary bypass, women exhibited a significantly higher incidence of diastolic dysfunction and longer hospital stays despite comparable baseline characteristics. Molecular analysis of atrial tissue revealed that men demonstrated increased postoperative PGC-1α and phosphorylated AMP-activated protein kinase (pAMPK), while women had reduced expression and also displayed a significant decline in myocardial NAD⁺ levels. To mechanistically model these findings, ovariectomized mice on a high-fat diet exhibited reduced myocardial PGC-1α and pAMPK expression, suppressed antioxidant defenses, and increased fibrosis. NAM supplementation restored myocardial NAD⁺, increased PGC-1α expression, and significantly improved systolic and diastolic cardiac function. These findings indicate that loss of estrogen impairs responses to oxidative stress in postmenopausal women, predisposing to adverse outcomes after cardiac stress. NAM may represent a promising non-hormonal strategy to restore mitochondrial function and improve cardiac function. This supports further evaluation of NAD⁺-boosting therapies as targeted interventions for postmenopausal women at risk of heart failure with preserved ejection fraction.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100831"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin use promotes pro-inflammatory changes in the transcriptome of atherosclerotic plaques in patients with diabetes mellitus","authors":"Angelle Bradford ,&nbsp;Tadashi Yoshida ,&nbsp;Sergiy Sukhanov ,&nbsp;Foster F. Woods ,&nbsp;Patrice Delafontaine ,&nbsp;Hernan A. Bazan ,&nbsp;T. Cooper Woods","doi":"10.1016/j.jmccpl.2025.100829","DOIUrl":"10.1016/j.jmccpl.2025.100829","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes Mellitus is associated with increased risk of myocardial infarctions and strokes due to accelerated atherosclerotic plaque development and rupture. The mechanisms driving plaque rupture in the diabetic setting remain unclear.</div></div><div><h3>Methods</h3><div>We sequenced ribosome-depleted total RNA from carotid plaques obtained from diabetic subjects undergoing carotid endarterectomy with high-grade stenosis, who either recently experienced a carotid-related ischemic cerebrovascular event (Symptomatic, <em>n</em> = 6) or had no such event (Asymptomatic, n = 6).</div></div><div><h3>Results</h3><div>Principal component analysis of the most variable transcripts demonstrated that sex and insulin use, rather than plaque rupture status, were the major contributors to the variability in the dataset. Hierarchical clustering further highlighted the importance of these factors in the dataset but also included two clusters whose expression was elevated in the symptomatic group. These clusters were enriched with transcripts for immunoglobulins and matrix metalloproteinases, suggesting increased B-cell infiltration and extracellular matrix degradation in the symptomatic plaques. We identified only two transcripts, <em>RNU2–1</em> and <em>PI4KAP1</em>, as significantly up-regulated in the symptomatic group. We identified 35 transcripts with altered expression in subjects on insulin therapy, including regulators of B-cells (<em>MZB1</em>), T cells (<em>BTN3A1, BTN3A2, BTN3A3, CD96</em>, and <em>CTSW</em>), and macrophages (<em>MPEG1</em>). Next, we used spatial deconvolution to focus on differentially expressed genes in the fibrous cap of the carotid plaques. In the symptomatic group, we identified elevated levels of five angiogenesis-associated transcripts (<em>ALS2CL, EPHB4, SMAD1, PREX2, EFNA5</em>), suggesting increased intraplaque neovascularization in ruptured plaques.</div></div><div><h3>Conclusions</h3><div>Thus, insulin use significantly impacts the transcriptome of atherosclerotic plaques, promoting vascular inflammation.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100829"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}