Journal of molecular and cellular cardiology最新文献

{"title":"Uncoupling protein 3 protects against pathological cardiac hypertrophy via downregulation of aspartate.","authors":"Yajun Wang, Jiliang Tan, Luxiao Li, Shenyan Liu, Xuxia Li, Huitong Shan, Huiyong Yin, Huang-Tian Yang","doi":"10.1016/j.yjmcc.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2025.03.001","url":null,"abstract":"<p><p>Metabolic remodeling involving alterations in the substrate utilization is a key feature of cardiac hypertrophy. However, the molecular mechanisms underlying regulation of tricarboxylic acid cycle intermediates by mitochondrial membrane proteins during cardiac hypertrophy have not yet been fully clarified. Mitochondrial uncoupling protein 3 (UCP3), an anion transporter located on the inner mitochondrial membrane, exerts cardioprotective effects against ischemia/reperfusion injury and its insufficiency exacerbates left ventricular (LV) diastolic dysfunction during hypertension. However, its role in pressure overload-induced cardiac hypertrophy remains unknown. Here, we found that UCP3 was downregulated in the mouse LV with transverse aortic constriction (TAC)-induced pathological hypertrophy and in phenylephrine (PE)-stimulated hypertrophic neonatal rat cardiomyocytes (NRCMs). The TAC-induced hypertrophy and LV dysfunction were aggravated in global and cardiac specific knockout of UCP3 (UCP3cKO) mice but improved by cardiac specific overexpression of UCP3 (UCP3cOE). Similar alterations in hypertrophy were observed in PE-treated NRCMs with UCP3-knockdown/overexpression. Moreover, the TAC-increased aspartate and glutamic-oxaloacetic transaminase 2 (GOT2) activity were enhanced in UCP3cKO hearts but reversed in UCP3cOE ones. PE-induced increases of GOT2 activity were enhanced in the UCP3-knockdown NRCMs but attenuated in the UCP3 overexpression ones, accompanied with the downregulation of aspartate. The endogenous interaction of UCP3 and GOT2 was weakened in the PE-treated NRCMs compared with the PE-untreated cells. Furthermore, aspartate supplementation reversed the UCP3 overexpression-attenuated hypertrophy in the PE-stimulated NRCMs. In conclusion, UCP3 expression is downregulated in hypertrophic hearts and cardiomyocytes, whereas the increase of UCP3 mitigates cardiac hypertrophy by downregulation of the enhanced aspartate. These findings provide new knowledge for the function of UCP3 and therapeutic target for cardiac hypertrophy.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice” [Journal of Molecular and Cellular Cardiology 113 (2017) 39–50].","authors":"Karla Maria Pires ,&nbsp;Marcio Buffolo ,&nbsp;Christin Schaaf ,&nbsp;J. David Symons ,&nbsp;James Cox ,&nbsp;E. Dale Abel ,&nbsp;Craizzg H. Selzman ,&nbsp;Sihem Boudina","doi":"10.1016/j.yjmcc.2025.01.008","DOIUrl":"10.1016/j.yjmcc.2025.01.008","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Page 94"},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrin stimulation by collagen I at the progenitor stage accelerates maturation of human iPSC-derived cardiomyocytes","authors":"Carlos Barreto-Gamarra,&nbsp;Maribella Domenech","doi":"10.1016/j.yjmcc.2025.02.009","DOIUrl":"10.1016/j.yjmcc.2025.02.009","url":null,"abstract":"<div><div>Cell manufacturing challenges have hampered effective preclinical evaluations of mature cardiac cells derived from human-induced pluripotent stem cells (hiPSCs). These challenges mainly stem from standard differentiation methods yielding cardiac cells of an immature phenotype, low cell yields and the need for extended culture for enhanced maturation. Although the intricate relationship between extracellular matrix (ECM) components and integrin expression levels plays a pivotal role during heart development, the impact of differentiation and maturation of cardiac cells on integrin behavior has not been thoroughly studied. This study postulates that cardiac cell maturation is significantly influenced by the timing of integrin stimulation via cell-matrix interactions. We profiled integrin expression levels throughout the differentiation process of cardiac cells and assessed the effects of utilizing defined ECM components as culture substrates on cell adhesion, proliferation, differentiation, and maturation. Our findings reveal that integrins facilitate hiPSC adhesion to ECM coated culture surfaces and underscores dynamic alterations in integrin expression during cardiac cell differentiation. Remarkably, we observed significant enrichments in α2 and β1 collagen integrin levels at the progenitor and differentiated stages. These shifts in collagen integrin levels were associated with enhanced cell seeding efficiency on collagen-type I surfaces and altered population doubling times. The stimulation of collagen integrins at the progenitor stage markedly boosted cardiac cell maturation, demonstrated by a significant (∼3-fold) increase in cardiac troponin I expression compared to the standard method after 15 days of culture. Enhanced maturation levels were further supported by significant increases in sarcomere development, maturation gene expression, morphological features, improved beating potency, and fatty acid metabolism dependency. Cardiac maturation driven by collagen was abrogated upon inhibition of collagen integrins targeted with selective pharmacological blockers, affirming their indispensable role in maturation without affecting cardiac differentiation levels. Our work confirms that stimulating collagen integrins at the progenitor stage is a potential strategy to achieve rapid maturation of hiPSC-derived cardiac cells.</div></div><div><h3>Statement of significance</h3><div>This study offers a novel strategy guided by integrin expression levels for generating hiPSC-CMs with improved maturation features in a short culture period (&lt;16 days). The improvements in cardiac cell maturation were achieved by stimulating collagen type 1 integrin at the progenitor stage. The potential benefits of this method for regenerative cardiac repair will pave the way for the preclinical examination of mature cardiac cells in tissues to advance cell manufacturing and cardiac toxicity studies.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Pages 70-86"},"PeriodicalIF":4.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipotoxicity as a therapeutic target in the type 2 diabetic heart.","authors":"Trang Luong, Seonbu Yang, Jaetaek Kim","doi":"10.1016/j.yjmcc.2025.02.010","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2025.02.010","url":null,"abstract":"<p><p>Cardiac lipotoxicity, characterized by excessive lipid accumulation in the cardiac tissue, is a critical contributor to the pathogenesis of diabetic heart. Recent research has highlighted the key mechanisms underlying lipotoxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and cell apoptosis, which ultimately impair the cardiac function. Various therapeutic interventions have been developed to target these pathways, mitigate lipotoxicity, and improve cardiovascular outcomes in diabetic patients. Given the global escalation in the prevalence of diabetes and the urgent demand for effective therapeutic approaches, this review focuses on how targeting cardiac lipotoxicity may be a promising avenue for treating diabetes.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gain and loss of the centrosomal protein taxilin-beta influences cardiac proteostasis and stress","authors":"Jared M. McLendon ,&nbsp;Xiaoming Zhang ,&nbsp;Colleen S. Stein ,&nbsp;Leslie M. Baehr ,&nbsp;Sue C. Bodine ,&nbsp;Ryan L. Boudreau","doi":"10.1016/j.yjmcc.2025.02.008","DOIUrl":"10.1016/j.yjmcc.2025.02.008","url":null,"abstract":"<div><div>Centrosomes localize to perinuclear foci where they serve multifunctional roles, arranging the microtubule organizing center (MTOC) and anchoring ubiquitin proteasome system (UPS) machinery, as suggested by prior studies. In mature cardiomyocytes, centrosomal proteins redistribute into a specialized perinuclear cage-like structure, and a potential centrosomal-UPS interface has not been studied, despite established roles for UPS in cardiomyopathy. In addition, there have been no reports citing cardiomyocyte UPS dysfunction upon or after manipulation of centrosomal proteins. Taxilin-beta (Txlnb), a cardiomyocyte-enriched protein, belongs to a family of centrosome adapter proteins implicated in protein quality control. We hypothesize that Txlnb is part of the perinuclear centrosomal cage and regulates proteostasis in cardiomyocytes. Herein, we show that centrosome proteins, including Txlnb, have significantly broadly dysregulated RNA expressions in failing hearts; however, Txlnb protein levels appear to be unchanged. Reanalysis of Txlnb's interactome supports its involvement in cytoskeletal, microtubule, and UPS processes, particularly centrosome-related functions. Using gain and loss of function approaches, in cells and mice, we show that Txlnb is a novel regulator of cardiac proteostasis through its influence on UPS. Overexpressing Txlnb in cardiomyocytes reduces ubiquitinated protein accumulation and enhances proteasome activity during hypertrophy. Germline Txlnb knockout in mice increases ubiquitinated protein accumulation, decreases 26Sβ5 proteasome activity, and lowers cardiac mass with aging, indicating proteasomal insufficiency and altered cardiac growth. Loss of Txlnb worsens heart phenotypes in mouse models of cardiac proteotoxicity and pressure overload. Overall, our data implicate the centrosomal protein Txlnb as a novel regulator of cardiac proteostasis, highlighting the likely presence of an understudied and important centrosome-proteasome functional connection in cardiomyocytes.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Pages 56-69"},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental pressure overload induces a cardiac neoantigen specific humoral immune response","authors":"Sasha Smolgovsky ,&nbsp;Abraham L. Bayer ,&nbsp;Mark Aronovitz ,&nbsp;Kathleen M.M. Vanni ,&nbsp;Annet Kirabo ,&nbsp;David G. Harrison ,&nbsp;Pilar Alcaide","doi":"10.1016/j.yjmcc.2025.02.007","DOIUrl":"10.1016/j.yjmcc.2025.02.007","url":null,"abstract":"<div><div>Inflammation is a hallmark of heart failure (HF), however anti-inflammatory therapies have yet to translate clinically. T-cells are central to cardiac pathology in experimental models of HF with reduced and preserved ejection fraction (HFrEF and HFpEF), however their antigen requirements differ, as shown in previous studies. Here we demonstrate that pressure overload elicits a cardiac and lymphoid B-cell humoral response characterized by autoantibodies (AAbs) towards the same cardiac neoantigens that induce T-cells in an experimental model of HFrEF, a novel mechanism distinct from an experimental model of HFpEF.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Pages 87-93"},"PeriodicalIF":4.9,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges in assessing myofilament calcium sensitivity and contractile function in HFpEF","authors":"Vasco Sequeira,&nbsp;Christoph Maack","doi":"10.1016/j.yjmcc.2025.02.006","DOIUrl":"10.1016/j.yjmcc.2025.02.006","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Pages 52-55"},"PeriodicalIF":4.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mouse model of post-traumatic stress disorder negatively impacts cardiac homeostasis","authors":"Alexa Corker ,&nbsp;Miguel Troncoso ,&nbsp;Maya Learmonth ,&nbsp;Philip Broughton ,&nbsp;Sara J. Sidles ,&nbsp;Ryan Kelly ,&nbsp;Shaoni Dasgupta ,&nbsp;Thomas Dempster ,&nbsp;Kim Vu ,&nbsp;Amber Hazzard ,&nbsp;An Van Laer ,&nbsp;Rachel D. Penrod ,&nbsp;Jeffery A. Jones ,&nbsp;Amy D. Bradshaw ,&nbsp;Michael R. Zile ,&nbsp;Amanda C. LaRue ,&nbsp;Kristine Y. DeLeon-Pennell","doi":"10.1016/j.yjmcc.2025.01.011","DOIUrl":"10.1016/j.yjmcc.2025.01.011","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is a disabling psychological disorder characterized by chronic symptoms of intrusiveness, avoidance, and hyperarousal after a traumatic event. Retrospective studies have indicated PTSD increases the risk for cardiovascular disease (CVD) including arrhythmia, hypertension, and myocardial infarction. The goal of this study was to: 1) use a murine model of cued fear conditioning (inescapable foot shock, IFS) to develop a scoring method to distinguish a PTSD-like phenotype, and 2) use this model system to characterize the cardiac phenotype and function in mice with extreme PTSD-like behaviors. We compared 3 groups, controls, non-responders (NR), and PTSD-like mice at 2 time points [4-weeks and 8-weeks post-IFS] to compare left ventricular structure and function. Assessment of cardiac function showed both male and female PTSD-like mice had increased isovolumetric relaxation time at 8-weeks post-IFS, whereas only females demonstrated increases in E/e’, left atrial diameter, and decreased ejection fraction compared to control mice. Female PTSD-like mice also demonstrated increased interstitial fibrosis through picrosirius red staining and increased expression of fibrotic genes including <em>Col3a1</em> and <em>Lox</em>. Overall, our data indicated that mice displaying behavioral characteristics associated with PTSD present with sex-dependent diastolic dysfunction likely due, at least in part, to an activation of cardiac fibrosis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Pages 32-43"},"PeriodicalIF":4.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescence in situ hybridization protocol for cardiomyocytes","authors":"Zehao Yao ,&nbsp;Lina Bai ,&nbsp;Yu Nie","doi":"10.1016/j.yjmcc.2025.02.003","DOIUrl":"10.1016/j.yjmcc.2025.02.003","url":null,"abstract":"<div><div>Measuring cardiomyocyte nuclear ploidy is crucial for evaluating broader aspects of cardiac development, function, and disease progression. Fluorescence in situ hybridization (FISH) remains the gold standard for ploidy identification; however, its application in cardiomyocytes is hindered by their unique cellular complexities. Here, we describe a detailed cardiomyocyte-specific FISH (cardioFISH) protocol. CardioFISH incorporates a tailored enzymatic digestion strategy to enhance nuclear accessibility while preserving cellular integrity and minimizing sarcomere-derived autofluorescence. Additionally, we introduce a 3D nuclear visualization framework for comprehensive cardioFISH signal analysis, addressing the limitations imposed by the large nuclear dimensions of cardiomyocytes, where signals are frequently distributed across multiple imaging planes. This two-day cardioFISH protocol is applicable to various stages of cardiomyocyte development and provides a powerful tool for advancing studies of cardiomyocyte ploidy.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Pages 44-51"},"PeriodicalIF":4.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxic compound exercise improves cardiac function in Drosophila high fructose diet via KHK","authors":"Xu Ping,&nbsp;Qiufang Li,&nbsp;Meng Ding,&nbsp;Zhengwen Yu,&nbsp;Qin Yi,&nbsp;Yuepeng Li,&nbsp;Wenzhi Gu,&nbsp;Ping Zhang,&nbsp;Zike Zhang,&nbsp;Lan Zheng","doi":"10.1016/j.yjmcc.2025.02.005","DOIUrl":"10.1016/j.yjmcc.2025.02.005","url":null,"abstract":"<div><div>Overconsumption of fructose has been linked to the development of systemic metabolic and cardiac diseases, yet few studies have focused on the link between cardiac fructose metabolism and the development of heart disease. Low-oxygen complex exercise is considered an effective means of treating and preventing metabolic diseases and improving cardiac function, however, it is unclear, the link between low-oxygen complex exercise and high-fructose-induced heart disease. Therefore, the aim of this study was to investigate the effect of hypoxic complex exercise on heart disease on a high fructose diet. The results of the study found that hypoxic compound exercise improved the upregulation of inflammatory factor Upd3 and systemic fat accumulation in the heart induced by high fructose diet by inhibiting the expression of KHK gene in the heart; and it improved the impaired cardiac rhythmic function and pumping function, improved the disorder of myofilament fiber arrangement, reduced the level of cardiac oxidative stress, and reduced cardiac collagen deposition. In addition, cardiac KHK-specific knockdown had the same effect on high fructose diet hearts. Compared with single KHK cardiac-specific knockdown or hypoxic combination exercise, hypoxic combination exercise combined with KHK cardiac-specific knockdown was superior in improving the high-fructose diet-induced increase in arrhythmia index, systolic and diastolic dysfunction, and decrease in fractional shortening. Therefore, we conclude that hypoxic complex exercise improved high-fructose diet-induced cardiac rhythmic function and pumping dysfunction by reducing KHK expression.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"201 ","pages":"Pages 95-104"},"PeriodicalIF":4.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}