Yiqing Yang , Albert Dashi , Poh Loong Soong , Kun Han Lin , Wilson L.W. Tan , Bangfen Pan , Matias I. Autio , Zenia Tiang , Robin J.G. Hartman , Heming Wei , Matthew Andrew Ackers-Johnson , Bing Lim , Anna Walentinsson , Vidhya Vardharajan Iyer , Malin K.B. Jonsson , Roger S. Foo
{"title":"Long noncoding RNA VENTHEART is required for ventricular cardiomyocyte specification and function","authors":"Yiqing Yang , Albert Dashi , Poh Loong Soong , Kun Han Lin , Wilson L.W. Tan , Bangfen Pan , Matias I. Autio , Zenia Tiang , Robin J.G. Hartman , Heming Wei , Matthew Andrew Ackers-Johnson , Bing Lim , Anna Walentinsson , Vidhya Vardharajan Iyer , Malin K.B. Jonsson , Roger S. Foo","doi":"10.1016/j.yjmcc.2024.10.009","DOIUrl":"10.1016/j.yjmcc.2024.10.009","url":null,"abstract":"<div><h3>Rationale</h3><div>Cardiac-expressed long noncoding RNAs (lncRNAs) are important for cardiomyocyte (CM) differentiation and function. Several lncRNAs have been identified and characterized for early CM lineage commitment, however those in later CM lineage specification and maturation remain less well studied. Moreover, unique atrial / ventricular lncRNA expression has never been studied in detail.</div></div><div><h3>Objectives</h3><div>Here, we characterized a novel ventricular myocyte-restricted lncRNA, not expressed in atrial myocytes, and conserved only in primates.</div></div><div><h3>Methods and results</h3><div>First, we performed single cell RNA-seq on human pluripotent stem cell derived cardiomyocytes (hPSC-CM) at the late stages of 2, 6 and 12 weeks of differentiation. Weighted correlation network analysis identified core gene modules, including a set of lncRNAs highly abundant and predominantly expressed in the human heart. A lncRNA (we call <em>VENTHEART</em>, <em>VHRT</em>) co-expressed with cardiac maturation and ventricular-specific genes <em>MYL2</em> and <em>MYH7</em>, and was expressed in fetal and adult human ventricles, but not atria. CRISPR-mediated deletion of the <em>VHRT</em> gene led to impaired CM sarcomere formation and significant disruption of the ventricular CM gene program. Indeed, a similar disruption was not observed in <em>VHRT</em> KO hPSC-derived atrial CM, suggesting that <em>VHRT</em> exhibits only ventricular myocyte subtype-specific effects. Optical recordings validated that loss of <em>VHRT</em> significantly prolonged action potential duration at 90 % repolarization (APD<sub>90</sub>) for ventricular-like, but not atrial-like, CMs.</div></div><div><h3>Conclusion</h3><div>This reports the first lncRNA that is exclusively required for proper ventricular, and not atrial, CM specification and function.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 90-102"},"PeriodicalIF":4.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560950","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}
Rodney Littlejohn , Josue Zambrano-Carrasco , Jianqiu Zou , Yali Yao , Il-man Kim , Jiliang Zhou , Jie Li , Huabo Su
{"title":"Inhibition of cardiomyocyte neddylation impairs embryonic cardiac morphogenesis","authors":"Rodney Littlejohn , Josue Zambrano-Carrasco , Jianqiu Zou , Yali Yao , Il-man Kim , Jiliang Zhou , Jie Li , Huabo Su","doi":"10.1016/j.yjmcc.2024.10.006","DOIUrl":"10.1016/j.yjmcc.2024.10.006","url":null,"abstract":"<div><div>Heart development is a complex spatiotemporal process involving a series of orchestrated morphogenic events that result in the formation of an efficient pumping organ. How posttranslational mechanisms regulate heart development remains poorly understood. Therefore, we investigate how neddylation, the attachment of NEDD8 to target proteins, coordinates cardiogenesis. Abrogation of neddylation by deleting <em>Nae1</em> in the heart via <em>Sm22α</em><sup><em>Cre</em></sup> led to early embryonic lethality. Mutant hearts exhibited deficits in trabeculation and expansion of the compact layer due to reduced cardiomyocyte proliferation, which was linked to abnormal Notch signaling in the developing heart. Overall, our findings demonstrate an essential role for neddylation in cardiogenesis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 40-44"},"PeriodicalIF":4.9,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502283","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":"Stochastic and alternating pacing paradigms to assess the stability of cardiac conduction","authors":"Stephan De Waard, Helene Hinnen, Jan P. Kucera","doi":"10.1016/j.yjmcc.2024.10.007","DOIUrl":"10.1016/j.yjmcc.2024.10.007","url":null,"abstract":"<div><div>Reentry, the most common cause of severe arrhythmias, is initiated by slow conduction and conduction block. Hence, evaluating conduction velocity and conduction block is of primary importance. However, the assessment of cardiac conduction safety in experimental and clinical settings remains elusive. To identify markers of conduction instability that can be determined experimentally, we developed an approach based on new pacing paradigms. Conduction across a cardiac tissue expansion was assessed in computer simulations and in experiments using cultures of neonatal murine cardiomyocytes on microelectrode arrays. Simulated and in vitro tissues were paced at a progressively increasing rate, with stochastic or alternating variations of cycle length, until conduction block occurred. Increasing pacing rate led to conduction block near the expansion. When stochastic or alternating variations were introduced into the pacing protocol, the standard deviation and the amplitude of alternating variations of local conduction times emerged as markers of unstable conduction prone to block. In both simulations and experiments, conduction delays were prolonged at the expansion but increased only slightly during the pacing protocol. In contrast, these markers of instability increased several-fold, early before block occurrence. The first and second moments of these two metrics provided an estimation of the site of block and the accuracy of this estimation. Therefore, when beat-to-beat variations of pacing cycle length are introduced into a pacing protocol, the local variability of conduction permits to predict sites of block. Our pacing paradigms may have translational applications in clinical cardiac electrophysiology, particularly in identifying ablation targets during mapping procedures.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 20-33"},"PeriodicalIF":4.9,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502285","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}
Keira R. Hassel , Aaron M. Gibson , Jaroslava Šeflová , Ellen E. Cho , N. Scott Blair , Catherine D. Van Raamsdonk , Douglas M. Anderson , Seth L. Robia , Catherine A. Makarewich
{"title":"Another-regulin regulates cardiomyocyte calcium handling via integration of neuroendocrine signaling with SERCA2a activity","authors":"Keira R. Hassel , Aaron M. Gibson , Jaroslava Šeflová , Ellen E. Cho , N. Scott Blair , Catherine D. Van Raamsdonk , Douglas M. Anderson , Seth L. Robia , Catherine A. Makarewich","doi":"10.1016/j.yjmcc.2024.10.008","DOIUrl":"10.1016/j.yjmcc.2024.10.008","url":null,"abstract":"<div><div>Calcium (Ca<sup>2+</sup>) dysregulation is a hallmark feature of cardiovascular disease. Intracellular Ca<sup>2+</sup> regulation is essential for proper heart function and is controlled by the sarco/endoplasmic reticulum Ca<sup>2+</sup> ATPase (SERCA2a). Another-regulin (ALN) is a newly discovered cardiomyocyte-expressed SERCA2a inhibitor, suggesting cardiomyocyte Ca<sup>2+</sup>-handling is more complex than previously appreciated. To study the role of ALN in cardiomyocytes, we generated ALN null mice (knockout, KO) and found that cardiomyocytes from these animals displayed enhanced Ca<sup>2+</sup> cycling and contractility compared to wildtype (WT) mice, indicating enhanced SERCA2a activity. In vitro and in vivo studies show that ALN is post-translationally modified via phosphorylation on Serine 19 (S19), suggesting this contributes to its ability to regulate SERCA2a. Immunoprecipitation and FRET analysis of ALN-WT, phospho-deficient ALN (S19A), or phosphomimetic ALN (S19D) revealed that S19 phosphorylation alters the SERCA2a-ALN interaction, leading to relief of its inhibitory effects. Adeno-associated virus mediated delivery of ALN-WT or phospho-mutant ALN-S19A/D in ALN KO mice showed that cardiomyocyte-specific expression of phospho-deficient ALN-S19A resulted in increased SERCA2a inhibition characterized by reduced rates of cytoplasmic Ca<sup>2+</sup> clearance compared to ALN-WT and ALN-S19D expressing cells, further supporting a role for this phosphorylation event in controlling SERCA2a-regulation by ALN. Levels of ALN phosphorylation were markedly increased in cardiomyocytes in response to Gα<sub>q</sub> agonists (angiotensin II, endothelin-1, phenylephrine) and Gα<sub>q</sub>-mediated phosphorylation of ALN translated to increased Ca<sup>2+</sup> cycling in cardiomyocytes from WT but not ALN KO mice. Collectively, these results indicate that ALN uniquely regulates Ca<sup>2+</sup> handling in cardiomyocytes via integration of neuroendocrine signaling with SERCA2a activity.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 45-58"},"PeriodicalIF":4.9,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502281","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}
Ying-Huizi Shen , Dong Ding , Tian-Yu Lian , Bao-Chen Qiu , Yi Yan , Pei-Wen Wang , Wei-Hua Zhang , Zhi-Cheng Jing
{"title":"Panorama of artery endothelial cell dysfunction in pulmonary arterial hypertension","authors":"Ying-Huizi Shen , Dong Ding , Tian-Yu Lian , Bao-Chen Qiu , Yi Yan , Pei-Wen Wang , Wei-Hua Zhang , Zhi-Cheng Jing","doi":"10.1016/j.yjmcc.2024.10.004","DOIUrl":"10.1016/j.yjmcc.2024.10.004","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a fatal lung disease characterized by progressive pulmonary vascular remodeling. The initial cause of pulmonary vascular remodeling is the dysfunction of pulmonary arterial endothelial cells (PAECs), manifested by changes in the categorization of cell subtypes, endothelial programmed cell death, such as apoptosis, necroptosis, pyroptosis, ferroptosis, et al., overproliferation, senescence, metabolic reprogramming, endothelial-to-mesenchymal transition, mechanosensitivity, and regulation ability of peripheral cells. Therefore, it is essential to explore the mechanism of endothelial dysfunction in the context of PAH. This review aims to provide a comprehensive understanding of the molecular mechanisms underlying endothelial dysfunction in PAH. We highlight the developmental process of PAECs and changes in PAH and summarise the latest classification of endothelial dysfunction. Our review could offer valuable insights into potential novel EC-specific targets for preventing and treating PAH.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 61-77"},"PeriodicalIF":4.9,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502284","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}
Vivek P. Jani , Navid Koleini , Axel J. Fenwick , Thomas E. Sharp , Traci T. Goodchild , Joseph A. Hill , David J. Lefer , Anthony Cammarato , David A. Kass
{"title":"Cardiomyocyte myofilament function in common animal models of heart failure with preserved ejection fraction","authors":"Vivek P. Jani , Navid Koleini , Axel J. Fenwick , Thomas E. Sharp , Traci T. Goodchild , Joseph A. Hill , David J. Lefer , Anthony Cammarato , David A. Kass","doi":"10.1016/j.yjmcc.2024.10.005","DOIUrl":"10.1016/j.yjmcc.2024.10.005","url":null,"abstract":"<div><div>Human cardiomyocytes from very obese patients with heart failure and preserved ejection fraction (HFpEF) have markedly depressed calcium-activated tension and increased resting stiffness. To test if either are recapitulated by obese-HFpEF animal models, tension‑calcium and tension-sarcomere length relations were measured in myocytes from mice on a high fat diet (HFD) with L-NAME, ZSF1 rats, and Göttingen minipigs on HFD + DOCA (MP). Only MP myocytes displayed reduced Ca<sup>2+</sup>-activated tension, and none exhibited increased resting stiffness versus respective controls. Consistent with prior myofibrillar data, crossbridge attachment and detachment rates at matched tension were slower in rodent models, and detachment slower in MP.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 34-39"},"PeriodicalIF":4.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467884","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}
Jiajie Yan , Saugat Khanal , Yuanyuan Cao , Nikola Ricchiuti , Alma Nani , S.R. Wayne Chen , Michael Fill , Dan J. Bare , Xun Ai
{"title":"Alda-1 attenuation of binge alcohol-caused atrial arrhythmias through a novel mechanism of suppressed c-Jun N-terminal Kinase-2 activity","authors":"Jiajie Yan , Saugat Khanal , Yuanyuan Cao , Nikola Ricchiuti , Alma Nani , S.R. Wayne Chen , Michael Fill , Dan J. Bare , Xun Ai","doi":"10.1016/j.yjmcc.2024.10.003","DOIUrl":"10.1016/j.yjmcc.2024.10.003","url":null,"abstract":"<div><div>Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol consumption, and atrial fibrillation (AF) is the most common arrhythmia among HHS patients. AF is associated with substantial morbidity and mortality, making its prevention and treatment of high clinical interest. This study defines the anti-AF action of Alda-1 (an established cardioprotective agent) and the underlying mechanisms of the action in our well-characterized HHS and cellular models. We found that Alda-1 effectively eliminated binge alcohol-evoked Ca<sup>2+</sup> triggered activities (Ca<sup>2+</sup> waves, prolonged Ca<sup>2+</sup> transient diastolic decay) and arrhythmia inducibility in intact mouse atria. We then demonstrated that alcohol impaired human RyR2 channels (isolated from organ donors' hearts). The functional role of alcohol-caused RyR2 channel dysfunction in Ca<sup>2+</sup> triggered arrhythmic activities was evidenced in a unique transgenic mouse model with a loss-of-function mutation (RyR2<sup>E4872Q+/−</sup>). Alda-1 is known to activate aldehyde dehydrogenase 2 (ALDH2), a key enzyme in alcohol detoxification. However, we found an increased level of ALDH2 and a preserved normal balance of pro- <em>vs</em> anti-apoptotic signaling in binge alcohol exposed hearts and H9c2 differentiated myocytes, which suggests that the link of alcohol-ALDH2-apoptosis is unlikely to be a key factor leading to binge alcohol-evoked arrhythmogenicity. We have previously reported that binge alcohol-activated stress response kinase JNK2 causatively drives Ca<sup>2+</sup>-triggered atrial arrhythmogenicity. Here, we found that JNK2-specific inhibition in either isolated human RyR2 channels or intact mouse atria abolished alcohol-evoked RyR2 channel dysfunction and Ca<sup>2+</sup> triggered arrhythmic activities, suggesting a strong alcohol-JNK2-RyR2 interaction in atrial arrhythmogenicity. Furthermore, we revealed, for the first time, that Alda-1 suppresses JNK2 (but not JNK1) enzyme activity independently of ALDH2, which in turn alleviates binge alcohol-evoked Ca<sup>2+</sup> triggered atrial arrhythmogenesis. Our findings provide novel mechanistic insights into the anti-arrhythmic action of Alda-1 and suggest that Alda-1 represents a potential preventative agent for AF management for HHS patients.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 11-19"},"PeriodicalIF":4.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441101","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}
Zhongyan Chen , Xiujian Yu , Minxia Ke , Hao Li , Yun Jiang , Peng Zhang , Jiliang Tan , Nan Cao , Huang-Tian Yang
{"title":"Human embryonic stem cell-derived cardiovascular progenitor cells stimulate cardiomyocyte cell cycle activity via activating the PI3K/Akt pathway","authors":"Zhongyan Chen , Xiujian Yu , Minxia Ke , Hao Li , Yun Jiang , Peng Zhang , Jiliang Tan , Nan Cao , Huang-Tian Yang","doi":"10.1016/j.yjmcc.2024.10.002","DOIUrl":"10.1016/j.yjmcc.2024.10.002","url":null,"abstract":"<div><div>Promoting endogenous cardiomyocyte proliferation is crucial for repairing infarcted hearts. Implantation of human pluripotent stem cell-derived cardiovascular progenitor cells (hCVPCs) promotes healing of infarcted hearts. However, little is known regarding their impact on host cardiomyocyte proliferation. Here, we revealed that hCVPC implantation into mouse infarcted hearts induced dedifferentiation and cell cycle re-entry of host cardiomyocytes, which was further confirmed in vitro by hCVPC-conditioned medium. Mechanistically, the PI3K/Akt signaling pathway mediated hCVPC-induced cardiomyocyte cell cycle re-entry. The findings reveal the novel function of hCVPCs in triggering cardiomyocyte dedifferentiation and cell cycle activation and highlight a strategy utilizing cells at early developmental stages to rejuvenate adult cardiomyocytes.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 5-10"},"PeriodicalIF":4.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406433","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":"Assessing and interpreting diastolic function in animal models of heart disease","authors":"David A. Kass","doi":"10.1016/j.yjmcc.2024.10.001","DOIUrl":"10.1016/j.yjmcc.2024.10.001","url":null,"abstract":"<div><div>Increasing interest in identifying the causes of and treatments for heart failure with preserved ejection fraction and cardiac fibrosis has spawned a focus on measures of cardiac diastolic function. The methods, their underlying principals and mechanics, and caveats to their measurement were largely worked out decades ago, but some of this seems a bit forgotten as scientists working in the field now have backgrounds more in molecular and cellular biology. This perspective was spawned by seeing the growing number of studies where diastolic function analysis is a key parameter used to justify a given pre-clinical model or to show the consequences of a particular genetic or pharmacological therapy. The goals are to discuss what comprises and influences diastolic function, how it is measured, what the parameters mean and what their limitations are, and what comprises evidence for pathophysiologically meaningful diastolic dysfunction.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Pages 1-4"},"PeriodicalIF":4.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377969","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}