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

{"title":"Diabetes mellitus disrupts lncRNA Malat1 regulation of cardiac mitochondrial genome-encoded protein expression.","authors":"Andrew D Taylor, Quincy A Hathaway, Ethan M Meadows, Andrya J Durr, Amina Kunovac, Mark V Pinti, Chris C Cook, Brianna R Miller, Remi Nohoesu, Roxy Nicoletti, Hafsat O Alabere, Aaron R Robart, John M Hollander","doi":"10.1152/ajpheart.00607.2024","DOIUrl":"10.1152/ajpheart.00607.2024","url":null,"abstract":"<p><p>Understanding the cellular mechanisms behind diabetes-related cardiomyopathy is crucial as it is a common and deadly complication of diabetes mellitus. Dysregulation of the mitochondrial genome has been linked to diabetic cardiomyopathy and can be ameliorated by altering microRNA (miRNA) availability in the mitochondrion. Long noncoding RNAs (lncRNAs) have been identified to downregulate miRNAs. This study aimed to determine if diabetes mellitus impacts the mitochondrial localization of lncRNAs, their interaction with miRNAs, and how this influences mitochondrial and cardiac function. In mouse and human nondiabetic and type 2 diabetic cardiac tissue, RNA was isolated from purified mitochondria and sequenced (Ilumina HiSeq). Malat1 was significantly downregulated in both human and mouse cardiac mitochondria. The use of a mouse model with an insertional deletion of Malat1 transcript expression resulted in exacerbated systolic and diastolic dysfunction when evaluated in conjunction with a high-fat diet. The cardiac effects of a high-fat diet were countered in a mouse model with transgenic overexpression of Malat1. MiR-320a, a miRNA that binds to both mitochondrial genome-encoded gene NADH-ubiquinone oxidoreductase chain 1 (MT-ND1) as well as Malat1, was upregulated in human and mouse diabetic mitochondria. Conversely, MT-ND1 was downregulated in human and mouse diabetic mitochondria. Mice with an insertional inactivation of Malat1 displayed increased recruitment of both miR-320a and MT-ND1 to the RNA-induced silencing complex (RISC). In vitro pulldown assays of Malat1 fragments with conserved secondary structure confirmed binding capacity for miR-320a. In vitro Seahorse assays indicated that Malat1 knockdown and miR-320a overexpression impaired overall mitochondrial bioenergetics and Complex I functionality. In summary, the disruption of Malat1 presence in mitochondria, as observed in diabetic cardiomyopathy, is linked to cardiac dysfunction and mitochondrial genome regulation.<b>NEW & NOTEWORTHY</b> Currently, there is no known mechanism for the development of diabetes-related cardiac dysfunction. Previous evaluations have shown that mitochondria, specifically mitochondrial genome-encoded transcripts, are disrupted in diabetic cardiac cells. This study explores the presence of long noncoding RNAs (lncRNAs) such as Malat1 in cardiac mitochondria and how that presence is impacted by diabetes mellitus. Furthermore, this study will examine how the loss of Malat1 results in bioenergetic and cardiac dysfunction through mitochondrial transcriptome dysregulation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1503-H1518"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493027","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":"Characterization of a novel ovine model of hypertensive heart failure with preserved ejection fraction.","authors":"Joshua W-H Chang, Siyi Chen, Charlotte Hamilton, Julia Shanks, Mridula Pachen, Audrys Pauza, Bindu George, Rohit Ramchandra","doi":"10.1152/ajpheart.00548.2024","DOIUrl":"10.1152/ajpheart.00548.2024","url":null,"abstract":"<p><p>The lack of animal models that accurately represent heart failure with preserved ejection fraction (HFpEF) has been a major barrier to the mechanistic understanding and development of effective therapies for this prevalent and debilitating syndrome characterized by multisystem impairments. Herein, we describe the development and characterization of a novel large animal model of HFpEF in older, female sheep with chronic 2-kidney, 1-clip hypertension. At 6-wk post unilateral renal artery clipping, hypertensive HFpEF sheep had higher mean arterial pressure compared with similarly aged ewes without unilateral renal artery clipping (mean arterial pressure = 112.7 ± 15.9 vs. 76.0 ± 10.1 mmHg, <i>P</i> < 0.0001). The hypertensive HFpEF sheep were characterized by <i>1</i>) echocardiographic evidence of diastolic dysfunction (lateral e' = 0.11 ± 0.02 vs. 0.14 ± 0.04 m/s, <i>P</i> = 0.011; lateral E/e' = 4.25 ± 0.77 vs. 3.63 ± 0.54, <i>P</i> = 0.028) and concentric left ventricular hypertrophy without overt systolic impairment, <i>2</i>) elevated directly measured left ventricular end-diastolic pressure (13 ± 5 vs. 0.5 ± 1 mmHg, <i>P</i> = 2.1 × 10^-6), and <i>3</i>) normal directly measured cardiac output. Crucially, these hypertensive HFpEF sheep had impaired exercise capacity as demonstrated by their <i>1</i>) attenuated cardiac output (<i>P</i> = 0.001), <i>2</i>) augmented pulmonary capillary wedge pressure (<i>P</i> = 0.026), and <i>3</i>) attenuated hindlimb blood flow (<i>P</i> = 3.4 × 10^-4) responses, during graded treadmill exercise testing. In addition, exercise renal blood flow responses were also altered. Collectively, our data indicates that this novel ovine model of HFpEF may be a useful translational research tool because it exhibits similar and clinically relevant impairments as that of patients with HFpEF.<b>NEW & NOTEWORTHY</b> We show that older, female sheep with chronic 2-kidney, 1-clip hypertension have similar cardiac and noncardiac exercise hemodynamic abnormalities as patients with HFpEF. This clinically relevant, translatable, and novel large animal model of HFpEF may be useful for elucidating mechanisms and developing treatments for this increasingly common syndrome with few clinically impactful therapies.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1490-H1502"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638551","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":"Hypoxia-inducible factor-2α enhances neutrophil survival to promote cardiac injury following myocardial infarction.","authors":"Enzo B Piccolo, Zhi-Dong Ge, Mallory E Filipp, David P Sullivan, Edward B Thorp, Ronen Sumagin","doi":"10.1152/ajpheart.00392.2024","DOIUrl":"10.1152/ajpheart.00392.2024","url":null,"abstract":"<p><p>Heart failure is a major cause of mortality following myocardial infarction. Neutrophils are among the first immune cells to accumulate in the infarcted region. Although beneficial functions of neutrophils in heart injury are now appreciated, neutrophils are also well known for their ability to exacerbate inflammation and promote tissue damage. Myocardial infarction induces hypoxia, where hypoxia-inducible factors (HIFs) are activated and play critical roles in cellular functions. In this context, the role of <i>Hif2α</i> in neutrophils during myocardial infarction is unknown. Here, we demonstrate that neutrophil <i>Hif2α</i> deletion markedly attenuates myocardial infarct size, improves cardiac function, reduces neutrophil survival and tissue accumulation, and correlates with increased macrophage engulfment rates. Mechanistic studies revealed that <i>Hif2α</i> promotes neutrophil survival through binding to hypoxia response element (HRE) in the promoter region of <i>Birc2</i> to regulate expression of the prosurvival factor, cellular inhibitor of apoptosis protein-1 (cIAP1). Inhibition of cIAP1 in neutrophils using the pharmacological agent, Birinapant resulted in increased cell death, establishing a critical role of cIAP1 downstream of <i>Hif2α</i> in neutrophil survival. Taken together, our data demonstrate a protective effect of <i>Hif2α</i> deletion in neutrophils on cardiac injury outcomes through modulation of neutrophil cell survival.<b>NEW & NOTEWORTHY</b> <i>Hif2α</i> in neutrophils increases infarct size, cardiac dysfunction, and ventricular scar after myocardial infarction. <i>Hif2α</i> in neutrophils supports neutrophil survival via cIAP-1 signaling and delays macrophage engulfment.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1230-H1243"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339447","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":"Red blood cells as potential materials for microRNA biomarker study: overcoming heparin-related challenges.","authors":"Eftychia Kontidou, Rawan Humoud, Ekaterina Chernogubova, Michael Alvarsson, Lars Maegdefessel, Aida Collado, John Pernow, Zhichao Zhou","doi":"10.1152/ajpheart.00609.2024","DOIUrl":"10.1152/ajpheart.00609.2024","url":null,"abstract":"<p><p>microRNAs (miRNAs) have been intensively studied as valuable biomarkers in cardiometabolic disease. Typically, miRNAs are detected in plasma or serum, but the use of samples collected in heparinized tubes is problematic for miRNA studies using quantitative PCR (qPCR). Heparin and its derivatives interfere with qPCR-based analysis, leading to a substantial reduction or even complete loss of detectable miRNA levels. Given that red blood cells (RBCs) express abundant miRNAs, whose expression is altered in cardiometabolic disease, RBCs could serve as an attractive alternative in biomarker studies. Here, we aim to explore the stability of miRNAs in RBCs collected from whole blood with different anticoagulants and thereby the potential of RBCs as alternative materials for miRNA biomarker studies. miRNA profiling was performed in human RBCs via RNA sequencing, followed by qPCR validation of selected miRNAs in RBCs and plasma in both heparinized and EDTA tubes. RNA sequencing revealed abundant miRNA presence in RBCs isolated from blood collected in EDTA tubes. miR-210-3p, miR-21-5p, miR-16-5p, and miR-451a were detected at comparable levels in RBCs isolated from both heparinized and EDTA tubes but not in plasma from heparinized tubes. Of note, miR-210-3p levels were consistently lower in RBCs from individuals with type 2 diabetes compared with healthy controls, regardless of anticoagulant type, supporting their potential as biomarker materials. In conclusion, RBCs offer a promising alternative for miRNA biomarker studies, overcoming heparin-related challenges.<b>NEW & NOTEWORTHY</b> microRNAs are valuable biomarkers in cardiometabolic disease, but heparinized tubes hinder their detection because of qPCR interference. RBCs, which express abundant microRNAs like miR-210-3p, may serve as an alternative. microRNAs, including miR-210-3p, are consistently detectable in RBCs at comparable levels between heparinized and EDTA tubes. miR-210-3p levels in RBCs are similarly reduced in heparinized tubes of patients with type 2 diabetes. Thus, RBCs offer a promising solution for miRNA biomarker studies, overcoming heparin-related challenges.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1296-H1302"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456047","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":"<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":"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}