American journal of physiology. Heart and circulatory physiology最新文献

{"title":"<i>RRAGD</i> variants cause cardiac dysfunction in a zebrafish model.","authors":"Anastasia Adella, Faris Tengku, Francisco J Arjona, Sanne Broekman, Erik de Vrieze, Erwin van Wijk, Joost G J Hoenderop, Jeroen H F de Baaij","doi":"10.1152/ajpheart.00705.2023","DOIUrl":"10.1152/ajpheart.00705.2023","url":null,"abstract":"<p><p>The Ras-related GTP-binding protein D (<i>RRAGD</i>) gene plays a crucial role in cellular processes. Recently, <i>RRAGD</i> variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences of <i>RRAGD</i> variants at the organismal level are unknown. Therefore, this study investigated the impact of <i>RRAGD</i> variants on cardiac function using a zebrafish embryo model. Furthermore, the potential usage of rapamycin, an mTOR inhibitor, as a therapy was assessed in this model. Zebrafish embryos were injected with <i>RRAGD</i> p.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression of <i>RRAGD</i> mutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. In <i>RRAGD</i> S76L-injected embryos, lower survival and heartbeat were observed, whereas survival was unaffected in <i>RRAGD</i> P119R embryos. These observations were reversible following therapy with the mTOR inhibitor rapamycin. Moreover, no effects on electrolyte homeostasis were observed. Together, these findings indicate a crucial role of <i>RRAGD</i> in cardiac function. In the future, the molecular mechanisms by which <i>RRAGD</i> variants result in cardiac dysfunction and if the effects of rapamycin are specific for <i>RRAGD</i>-dependent cardiomyopathy should be studied in clinical studies.<b>NEW & NOTEWORTHY</b> The resultant heart-associated phenotypes in the zebrafish embryos of this study serve as a valuable experimental model for this rare cardiomyopathy. Moreover, the potential therapeutic property of rapamycin in cardiac dysfunctions was highlighted, making this study a pivotal step toward prospective clinical applications.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1187-H1197"},"PeriodicalIF":5.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339445","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":"USP20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.","authors":"Pierre-Yves Jean-Charles, Bipradas Roy, Samuel Mon-Wei Yu, Gianluigi Pironti, Karim Nagi, Lan Mao, Suneet Kaur, Dennis M Abraham, Stuart Maudsley, Howard A Rockman, Sudha K Shenoy","doi":"10.1152/ajpheart.00329.2024","DOIUrl":"10.1152/ajpheart.00329.2024","url":null,"abstract":"<p><p>Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well characterized. To define whether the deubiquitinase ubiquitin-specific peptidase 20 (USP20) regulates LVH, we subjected USP20 knockout (KO) and cognate wild-type (WT) mice to chronic pressure overload by transverse aortic constriction (TAC) and measured changes in cardiac function by serial echocardiography followed by histological and biochemical evaluations. USP20-KO mice showed severe deterioration of systolic function within 4 wk of TAC compared with WT cohorts. Both USP20-KO TAC and WT-TAC cohorts presented cardiac hypertrophy following pressure overload. However, USP20-KO-TAC mice showed an increase in cardiomyocyte length and developed maladaptive eccentric hypertrophy, a phenotype generally observed with volume overload states and decompensated heart failure. In contrast, WT-TAC mice displayed an increase in cardiomyocyte width, producing concentric remodeling that is characteristic of pressure overload. In addition, cardiomyocyte apoptosis, interstitial fibrosis, and mouse mortality were augmented in USP20-KO-TAC compared with WT-TAC mice. Quantitative mass spectrometry of LV tissue revealed that the expression of sarcomeric myosin heavy chain 7 (MYH7), a fetal gene normally upregulated during cardiac remodeling, was significantly reduced in USP20-KO after TAC. Mechanistically, we identified increased degradative lysine-48 polyubiquitination of MYH7 in USP20-KO hearts, indicating that USP20-mediated deubiquitination likely prevents protein degradation of MYH7 during pressure overload. Our findings suggest that USP20-dependent signaling pathways regulate the layering pattern of sarcomeres to suppress maladaptive remodeling during chronic pressure overload and prevent cardiac failure.<b>NEW & NOTEWORTHY</b> We identify ubiquitin-specific peptidase 20 (USP20) as an important enzyme that is required for cardiac homeostasis and function, particularly during myocardial pressure overload. USP20 regulates protein stability of cardiac MYH7, an essential molecular motor protein expressed in sarcomeres; loss-of-function mutations of <i>MYH7</i> are associated with human hypertrophic cardiomyopathy, cardiac failure, and sudden death. Enhancing USP20 activity could be a potential therapeutic approach to prevent the development of maladaptive state of eccentric hypertrophy and heart failure.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1257-H1271"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374888","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":"Reduced microvascular flow-mediated dilation in Syrian hamsters lacking d-sarcoglycan is caused by increased oxidative stress.","authors":"Alexis Richard, Arnaud Bocquet, Eric Belin de Chantemèle, Kevin Retailleau, Bertrand Toutain, Héloïse Mongue-Din, Anne-Laure Guihot, Celine Fassot, Yves Fromes, Daniel Henrion, Laurent Loufrani","doi":"10.1152/ajpheart.00569.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00569.2024","url":null,"abstract":"<p><p>d-sarcoglycan mutation reduces mechanotransduction and induces dilated cardiomyopathy with aging. We hypothesized that in young hamsters with d-sarcoglycan mutation, which do not show cardiomyopathy, flow mechanotransduction might be affected in resistance arteries as the control of local blood flow. Flow-mediated-dilation (FMD) was measured in isolated mesenteric resistance arteries, using 3-months old hamsters carrying a mutation in the d-sarcoglycan gene (CH-147) and their control littermates. The FMD was significantly reduced in the CHF-147 group. Nevertheless, passive arterial diameter, vascular structure and endothelium-independent dilation to sodium nitroprusside were not modified. Contraction induced by KCl was not modified, whereas contraction due to phenylephrine was increased. The basal NO production and total eNOS expression levels were not altered. Nevertheless, eNOS phosphorylation, FAKs and RhoA expression were reduced in CH-147. In contrast, p47phox, COX2, iNOS and reactive oxygen species levels were higher in the endothelium of CHF-147 hamsters. Reducing ROS levels using the superoxide dismutase analog Tempol significantly restored the flow-mediated dilation (FMD) levels in CHF-147 hamsters. However, treatment with the COX-2 inhibitor NS-398 showed a non-significant improvement in FMD.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556962","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":"Heart failure with preserved ejection fraction in pigs causes shifts in posttranscriptional checkpoints.","authors":"Stephanie L Samani, Shayne C Barlow, Lisa A Freeburg, Grayson M Catherwood, Amelia M Churillo, Traci L Jones, Diego Altomare, Hao Ji, Michael Shtutman, Michael R Zile, Tarek Shazly, Francis G Spinale","doi":"10.1152/ajpheart.00551.2023","DOIUrl":"10.1152/ajpheart.00551.2023","url":null,"abstract":"<p><p>Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV <i>K</i>_c) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (<i>n</i> = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (<i>n</i> = 6) served as controls. LV function was measured by echocardiography and LV <i>K</i>_c by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (<i>n</i> = 10, <i>n</i> = 9, respectively). LV samples from LVPO and controls (<i>n</i> = 6, respectively) were subjected to RNA sequencing. LV mass and <i>K</i>_c increased by over 40% with LVPO (<i>P</i> < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV <i>K</i>_c (<i>P</i> < 0.05) that mapped to functional domains relevant to <i>K</i>_c such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (<i>P</i> < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.<b>NEW & NOTEWORTHY</b> Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1272-H1285"},"PeriodicalIF":5.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139041","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":"Cellular calcium handling and electrophysiology are modulated by chronic physiological pacing in human induced pluripotent stem cell-derived cardiomyocytes.","authors":"Maria Knierim, Thea Bommer, Michael Paulus, Dominic Riedl, Sarah Fink, Arnold Pöppl, Florian Reetz, Peter Wang, Lars S Maier, Niels Voigt, Matthias Nahrendorf, Samuel Sossalla, Katrin Streckfuss-Bömeke, Steffen Pabel","doi":"10.1152/ajpheart.00536.2024","DOIUrl":"10.1152/ajpheart.00536.2024","url":null,"abstract":"<p><p>Electric pacing of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) has been increasingly used to simulate cardiac arrhythmias in vitro and to enhance cardiomyocyte maturity. However, the impact of electric pacing on cellular electrophysiology and Ca²⁺ handling in differentiated hiPSC-CM is less characterized. Here we studied the effects of electric pacing for 24 h or 7 days at a physiological rate of 60 beats/min on cellular electrophysiology and Ca²⁺ cycling in late-stage, differentiated hiPSC-CM (>90% troponin⁺, >60 days postdifferentiation). Electric culture pacing for 7 days did not influence cardiomyocyte cell size, apoptosis, or generation of reactive oxygen species in differentiated hiPSC-CM compared with 24-h pacing. However, epifluorescence measurements revealed that electric pacing for 7 days improved systolic Ca²⁺ transient amplitude and Ca²⁺ transient upstroke, which could be explained by elevated sarcoplasmic reticulum Ca²⁺ load and SERCA activity. Diastolic Ca²⁺ leak was not changed in line-scanning confocal microscopy, suggesting that the improvement in systolic Ca²⁺ release was not associated with a higher open probability of ryanodine receptor (RyR)2 during diastole. Whereas bulk cytosolic Na⁺ concentration and Na⁺/Ca²⁺ exchanger (NCX) activity were not changed, patch-clamp studies revealed that chronic pacing caused a slight abbreviation of the action potential duration (APD) in hiPSC-CM. We found in whole cell voltage-clamp measurements that chronic pacing for 7 days led to a decrease in late Na⁺ current, which might explain the changes in APD. In conclusion, our results show that chronic pacing improves systolic Ca²⁺ handling and modulates the electrophysiology of late-stage, differentiated hiPSC-CM. This study might help to understand the effects of electric pacing and its numerous applications in stem cell research including arrhythmia simulation.<b>NEW & NOTEWORTHY</b> Electric pacing is increasingly used in research with human induced pluripotent stem cell cardiomyocytes (hiPSC-CM), for example to simulate arrhythmias but also to enhance maturity. Therefore, it is mandatory to understand the effects of pacing itself on cellular electrophysiology in late-stage, matured hiPSC-CM. This study provides an electrophysiological characterization of the effects of chronic electric pacing at a physiological rate on differentiated hiPSC-CM.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1244-H1254"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279127","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":"Activation of IP₃R in atrial cardiomyocytes leads to generation of cytosolic cAMP.","authors":"Tatum M Weishaar, Beth A Habecker","doi":"10.1152/ajpheart.00557.2024","DOIUrl":"10.1152/ajpheart.00557.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1153-H1154"},"PeriodicalIF":5.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987292","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":"The importance of myosin ubiquitination status for cardiac remodeling: USP20 has entered the chat.","authors":"Thomas G Martin","doi":"10.1152/ajpheart.00712.2024","DOIUrl":"10.1152/ajpheart.00712.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1306-H1308"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493036","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":"Ebbs and tides of endothelial K⁺ currents that regulate blood flow.","authors":"Paige E Martin, Paulo W Pires","doi":"10.1152/ajpheart.00678.2024","DOIUrl":"10.1152/ajpheart.00678.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1205-H1207"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399138","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":"The pH-sensing GPR68 and Rap1A: new kids in the arterial remodeling block.","authors":"Jade L Taylor, Nuria Daghbouche-Rubio, Miguel Martín-Aragón Baudel","doi":"10.1152/ajpheart.00671.2024","DOIUrl":"10.1152/ajpheart.00671.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1208-H1209"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399139","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":"Early Pathological Mechanisms in a Mouse Model of Heart Failure with Preserved Ejection Fraction.","authors":"Paola C Rosas, Liomar A A Neves, Nisha Patel, Duyen Tran, Carlos H Pereira, Karina R Bonilla, Jingjing Zheng, Jun Sun, Francisco J Alvarado, Kathrin Banach","doi":"10.1152/ajpheart.00318.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00318.2024","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all HF cases, yet evidence-based therapies remain lacking due to limited understanding of its underlying pathological mechanisms. Our study aimed to uncover early pathological mechanisms in HFpEF by exposing mice to dietary conditions resembling a Western diet-rich in fats, salt, and low in fiber-alongside excess mineralocorticoids to replicate significant aspects of human HFpEF. Echocardiography was performed at both 3-week and 6-week intervals post-challenge, revealing cardiac alterations as early as 3-weeks. While ejection fraction remained preserved, mice exhibited signs of diastolic dysfunction, reduced stroke volume, and left atrial enlargement. Additionally, changes in pulmonary flow velocities were noted by the 3-week mark, suggesting elevated pulmonary pressure. Extracardiac comorbidities included organ congestion, increased adiposity, impaired glucose tolerance, and hypercholesterolemia. Molecular analyses unveiled evidence of low-grade inflammation, oxidative stress, and impaired NO-cGMP-PKG signaling, contributing to the observed decrease in titin phosphorylation, thereby impacting myocardial stiffness. Additionally, impaired NO signaling might have influenced the alterations observed in coronary flow reserve. Moreover, dysregulation of calcium signaling in cardiomyocytes and reduced SR load were observed. Interestingly, elevated phosphorylation of cMyBP-C was linked to preserved ejection fraction despite reduced SR load. We also observed intestinal atrophy, possibly due to low dietary fiber intake and diminished gut perfusion, potentially contributing to systemic low-grade inflammation. These findings reveal how excess mineralocorticoids-salt-induced hypertension, and dietary factors, like high-fat and low-fiber intake, contribute to cardiac dysfunction and metabolic disturbances, offering insights into early HFpEF pathology in this model.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556958","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}