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

{"title":"Sustained tenascin-C expression drives neointimal hyperplasia and promotes aortocaval fistula failure.","authors":"Luis A Gonzalez, Weichang Zhang, Hualong Bai, Ryosuke Taniguchi, Abhay B Ramachandra, Daniel G Jovin, Yuichi Ohashi, Mytien Nguyen, Carly Thaxton, Bogdan Yatsula, Roberto I Vazquez-Padron, Jay D Humphrey, Kathleen A Martin, Themis R Kyriakides, Alan Dardik","doi":"10.1152/ajpheart.00661.2024","DOIUrl":"10.1152/ajpheart.00661.2024","url":null,"abstract":"<p><p>End-stage kidney disease (ESKD) impacts over 740,000 individuals in the United States, with many patients relying on arteriovenous fistulae (AVF) for hemodialysis due to superior patency and reduced infections. However, AVF patency is reduced by thrombosis and neointimal hyperplasia, yielding a 1-yr patency of only 40%-50%. We hypothesized that tenascin-C (TNC), a regulator of inflammation and immune responses after injury, also regulates venous remodeling during AVF maturation. AVF were created in wild-type (WT) and <i>Tnc</i> knockout (<i>Tnc</i>^-/-) mice, and proteomic analyses were conducted to identify protein changes between sham and AVF WT tissue. Immunofluorescence and Western blot assays compared venous tissue from WT and <i>Tnc</i>^-/- mice. In vitro studies using human umbilical vein endothelial cells and human umbilical vein smooth muscle cells examined TNC-siRNA effects on thrombomodulin (THBD) and NF-κB. Macrophages from WT and <i>Tnc</i>^-/- mice were assessed for anti-inflammatory phenotype polarization and tissue factor expression. TNC expression was spatially and temporally regulated in WT mice with AVF, and TNC colocalized with matrix remodeling but not with THBD expression; TNC expression was downregulated in patent AVF but sustained in occluded AVF, both in WT mice and human AVF specimens. <i>Tnc</i>^-/- mice had reduced AVF patency, less wall thickening, and increased thrombosis, with increased THBD expression. In vitro, TNC-siRNA increased THBD and reduced NF-κB activation. Macrophages from <i>Tnc</i>^-/- mice showed increased anti-inflammatory macrophage polarization and tissue factor expression, facilitating thrombosis. Sustained TNC expression drives neointimal hyperplasia and AVF failure by promoting a prothrombotic, inflammatory microenvironment. Targeting TNC pathways may enhance AVF patency and improve dialysis outcomes.<b>NEW & NOTEWORTHY</b> This study identifies Tenascin-C (TNC) as a key regulator of arteriovenous fistula (AVF) patency. TNC is spatially and temporally regulated, driving neointimal hyperplasia and thrombosis by promoting a prothrombotic, inflammatory microenvironment. In <i>Tnc</i>^-/- mice, reduced TNC expression increased thrombomodulin and anti-inflammatory macrophage polarization but impaired wall thickening and AVF patency. These findings link sustained TNC expression to AVF failure and suggest that targeting TNC pathways could enhance AVF outcomes in patients requiring hemodialysis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1147-H1167"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953864","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":"PVAT adipocyte: energizing, modulating, and structuring vascular function during normotensive and hypertensive states.","authors":"C Javier Rendon, Stephanie W Watts, G Andres Contreras","doi":"10.1152/ajpheart.00093.2025","DOIUrl":"10.1152/ajpheart.00093.2025","url":null,"abstract":"<p><p>Hypertension represents the most common form of cardiovascular disease. It is characterized by significant remodeling of the various layers of the vascular system, including the outermost layer: the perivascular adipose tissue (PVAT). Given the tissue's pivotal role in regulating blood pressure, a comprehensive understanding of the changes that occur within PVAT during the progression of hypertension is essential. This article reviews the mechanisms through which PVAT modulates blood pressure, including the secretion of bioactive soluble factors, provision of mechanical support, and adipose-specific functions such as adipogenesis, lipogenesis, lipolysis, and extracellular matrix remodeling. Additionally, this review emphasizes the influence of hypertension on each of these regulatory mechanisms, thereby providing a deeper insight into the pathophysiological interplay between hypertension and PVAT biology.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1204-H1217"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962253","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":"Associations of circulating T cell subsets with endothelial function: the Multi-Ethnic Study of Atherosclerosis.","authors":"Theodore M DeConne, Colleen M Sitlani, Kevin P Decker, Joseph A Delaney, Bruce M Psaty, Margaret F Doyle, Petra Buzkova, Alan L Landay, Sally A Huber, Timothy M Hughes, David Herrington, Jingzhong Ding, Nels C Olson","doi":"10.1152/ajpheart.00893.2024","DOIUrl":"10.1152/ajpheart.00893.2024","url":null,"abstract":"<p><p>Endothelial dysfunction has emerged as a risk factor for many age-related diseases such as cardiovascular disease and Alzheimer's disease and related dementias. T-lymphocytes (T cells) have been identified as important regulators of endothelial function in multiple murine models, and proinflammatory and senescent T cell subsets have been associated with endothelial dysfunction in middle-aged adults with hypertension. However, there is little data on the relationships between T cell subsets and endothelial function in large, multi-ethnic, population-based cohorts free from cardiovascular diseases. Therefore, the purpose of this study was to determine whether T cell subsets were associated with endothelial function in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery by duplex ultrasound at the baseline examination. Baseline peripheral blood T cell subsets were measured using flow cytometry (<i>n</i> = 968). Two analyses were used. The primary analysis examined associations of Th1 [CD4⁺ interferon-γ⁺ (IFN-γ⁺)] and CD4⁺CD28^-CD57⁺ T cells, specified as a priori hypotheses, with FMD using multivariable linear regression. Secondary analyses examined associations between 27 additional immune cell populations with FMD. Th1 and CD4⁺CD28^-CD57⁺ T cells were not associated with FMD. In secondary analyses, a 1-SD higher value of pan CD4⁺ and pan CD8⁺ T cells were associated with lower and higher FMD, respectively. These results may suggest regulation of endothelial function by T cells in preclinical models is conserved in humans. The findings warrant additional longitudinal human studies with greater T-cell phenotyping to further understand the influence of CD4⁺ and CD8⁺ T cell balance on endothelial function.<b>NEW & NOTEWORTHY</b> We investigated whether peripheral T cells were associated with endothelial function in a multi-ethnic cohort. No significant associations were observed between Th1 or CD4⁺CD28-CD57⁺ T cells with endothelial function in the primarily analysis. A higher value of pan CD4⁺ T cells was associated with lower endothelial function, while a higher value of pan CD8⁺ T cells was associated with higher endothelial function in the secondary analysis. This study provides epidemiological data linking pan T cells to measures of endothelial function.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1374-H1379"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389653","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":"Structural and functional adaptations of human cardiomyocytes in metabolic disease and heart failure.","authors":"Judith Huettemeister, Markus Bögner, Dirk Eggert-Doktor, Emanuel Heil, Uwe Primessnig, Sophie C Reimers, Marzena Kirk, Girish Ramesh, Timo Zadegh Nazari-Shafti, Herko Grubitzsch, Simon Sündermann, Christoph Knosalla, Kun Zhang, Volkmar Falk, Frank R Heinzel, Felix Hohendanner","doi":"10.1152/ajpheart.00903.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00903.2024","url":null,"abstract":"<p><p>Heart failure (HF), obesity, and diabetes are associated with structural and functional changes that affect the heart at both the organ and cellular levels. Studying isolated adult single cardiomyocytes provides valuable mechanistic insights. However, isolating single cardiomyocytes from human tissue is particularly challenging. This study presents an optimized multiple-step digestion protocol to isolate viable cardiomyocytes from atrial and ventricular human tissue obtained perioperatively or through myocardial biopsies. Using this method and resource, we analyzed calcium-signaling during excitation-contraction coupling and structural features such as t-tubules and mitochondria using confocal microscopy in patients with or without HF, obesity, or diabetes. In a subset of patients undergoing open heart surgery, tissue samples and serum from the great cardiac vein were obtained either under control conditions or upon cardiac volume challenge (VC). We isolated viable cells and observed distinct structural differences between atrial and ventricular cardiomyocytes, including variations in t-tubular and cell size. In atrial cardiomyocytes, when comparing control with patients with HF, the t-tubular networks were unchanged. However, patients with obesity exhibited significantly more t-tubules associated with larger cell sizes. Furthermore, mitochondrial density appeared higher in patients with overweight and diabetes, suggesting that the metabolic status influences cardiomyocyte structure. Finally, when exposing isolated cardiomyocytes with VC serum from the respective patients, excitation-contraction coupling was markedly enhanced, indicating a distention-related alteration of the cardiac secretome with immediate effects on cardiomyocytes. In summary, an optimized protocol for isolating human cardiomyocytes confirmed structural features, identified disease-related changes, and allowed studying the dynamic impact of cardiac distention on secretome-related cardiomyocyte function.<b>NEW & NOTEWORTHY</b> This study presents a novel protocol for isolating human cardiomyocytes, uncovering atrial-ventricular structural differences, obesity-related increases in t-tubules and mitochondria, and metabolic influences on cell architecture. It highlights the dynamic effects of cardiac volume challenge on excitation-contraction coupling through secretome alterations. These advancements provide insights into how conditions like obesity and diabetes reshape cardiomyocyte structure and function, advancing our understanding of heart disease mechanisms.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1193-H1203"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971116","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":"Regional left ventricular wall stress postmyocardial infarction with magnetic resonance imaging in swine.","authors":"Jacob Ref, Eli Lefkowitz, Amal Anilkumar, Satya Acharya, Adrian Grijalva, Grace Gorman, Sherry Daugherty, Kenneth Fox, Jordan J Lancaster, Tushar Acharya, Michael J Moulton, Ryan Avery, Steven Goldman","doi":"10.1152/ajpheart.00120.2025","DOIUrl":"10.1152/ajpheart.00120.2025","url":null,"abstract":"<p><p>This study presents a novel approach to measure regional left ventricular (LV) wall stress using cardiac magnetic resonance (CMR) imaging. We studied a chronic heart failure (CHF) model in Yucatan mini swine. Animals underwent 90-min balloon occlusion and reperfusion of the left anterior descending (LAD) coronary artery. LV pressures were measured using solid-state micromanometer pressure-tipped catheters. End-systolic elastance, end-diastolic pressure-volume relationships, and CMR imaging were collected at baseline and 1-mo postmyocardial infarction (MI). One month post-MI, data showed reduced LV function with increased end-systolic volume, end-diastolic volume, LV myocardial mass, and reduced ejection fraction. Hemodynamic data showed no significant changes in heart rate, LV pressures, tau, or LV dP/d<i>t</i>. However, end-systolic elastance decreased significantly (1.8 ± 0.2 to 1.1 ± 0.1, <i>P</i> < 0.05), indicating reduced LV contractility. Regional LV wall stress calculations revealed increasing trends in anterior septal (anteroseptal) and posterior lateral (posterolateral) end-systolic wall stress (ESWS). Anteroseptal ESWS increased from 10.1 ± 2.0 kPa to 20.0 ± 3.3 kPa (<i>P</i> < 0.05), whereas posterolateral ESWS increased from 6.8 ± 0.3 kPa to 11.7 ± 1.4 kPa (<i>P</i> < 0.05). This study demonstrates the benefit of a regional approach to LV wall stress assessment. Our findings revealed significant changes in both the anteroseptal (involved) and posterolateral (uninvolved) regions, suggesting a widespread impact of localized injury. Regional wall stress calculations can assess cardiac damage and provide prognosis of injury extent, potentially offering insights into global LV remodeling post-MI.<b>NEW & NOTEWORTHY</b> This study introduces a novel approach to assess regional left ventricular wall stress using cardiac MRI in a clinically relevant model of myocardial infarction. We demonstrate that postinfarction remodeling leads to increased wall stress not only in the infarcted region but also in remote myocardium. This regional analysis method provides mechanistic insights into the widespread mechanical impact of localized injury and could inform future investigations into the pathophysiology of adverse remodeling following myocardial infarction.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1391-H1399"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965334","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":"Muscle-specific isoforms of FXR1 are necessary for miR-1-mediated repression of connexin 43 and are downregulated in pediatric dilated cardiomyopathy.","authors":"Danielle A Jeffrey, Karen Dockstader, Amanda Revoredo Vicentino, Dobromir B Slavov, Shelley D Miyamoto, Brian L Stauffer, Carmen C Sucharov","doi":"10.1152/ajpheart.00885.2024","DOIUrl":"10.1152/ajpheart.00885.2024","url":null,"abstract":"<p><p>The Fragile-X (FraX) protein family regulates RNA metabolism, muscle development, and neuronal plasticity. These proteins are crucial for translation regulation, interacting with ribosomal subunits and RNA through specific domains. FXR1 has seven isoforms, including isoforms mostly expressed in skeletal and cardiac tissue, and plays a significant role in heart development and function. Additionally, FXR1 modulates microRNA function, impacting gene expression. Given FXR1's crucial role in cardiac differentiation, we evaluated whether expression of the muscle-specific isoforms of FXR1 was dysregulated in pediatric dilated cardiomyopathy (DCM) and sought to determine the impact of these isoforms on the function of miR-1, an important cardiac miRNA, and its regulation of the 3' untranslated region (3' UTR) of the gap junction protein connexin 43 (Cx43). Our results show that FXR1 protein levels are decreased in pediatric DCM left ventricular tissue compared to age-matched nonfailing controls. We investigated the function of muscle-specific isoforms FXR1-G and FXR1-E in an in vitro model of myocyte differentiation. H9c2 cells, differentiated to cardiomyocyte-like cells, show a significant increase in FXR1-G/E protein expression compared to H9c2 myoblasts. Furthermore, we show that FXR1G/E are essential for miR-1-mediated repression of Cx43 3' UTR, emphasizing the importance of miR binding proteins in myocyte homeostasis. Finally, we show that FXR1-G promotes interaction between miR-1 and the Cx43 3' UTR. Overall, we demonstrate that miR-1 regulation of the Cx43 3' UTR relies on muscle-specific isoforms of FXR1. Significantly, we are the first to report a reduction in the muscle-specific isoforms of FXR1 in pediatric DCM patients, underscoring an age-specific regulation of FXR1 expression.<b>NEW & NOTEWORTHY</b> The contribution of microRNAs to cardiovascular diseases has been extensively studied. However, the ability of microRNAs to regulate gene expression requires interactions with RNA-binding proteins (RBPs). Little is known about the contribution of RBPs to microRNA regulation in muscle. We now show that the muscle-specific isoforms of the RBP FXR1 are decreased in pediatric dilated cardiomyopathy hearts and are necessary for miR-1 repression of connexin 43 3' untranslated region (3' UTR), highlighting the importance of RBPs in miRNA function.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1380-H1390"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958907","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":"lncRNAs in vascular senescence and microvascular remodeling.","authors":"Warlley Rosa Cunha, Maria Martin de la Vega, Paula Rodrigues de Barros, Cristina Espinosa-Diez","doi":"10.1152/ajpheart.00750.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00750.2024","url":null,"abstract":"<p><p>Long noncoding RNAs (lncRNAs) have emerged as critical regulators of vascular senescence and microvascular remodeling, processes that significantly contribute to the development of age-related diseases in organs such as the kidneys, heart, and lungs. Through mechanisms like chromatin remodeling, transcriptional regulation, and posttranscriptional modifications, lncRNAs modulate gene expression, thereby influencing cellular processes such as apoptosis, inflammation, fibrosis, and angiogenesis. In chronic kidney disease, cardiovascular disease, and pulmonary disorders, lncRNAs play a central role in promoting vascular dysfunction, endothelial cell aging, and fibrosis. This review focuses on how lncRNAs contribute to endothelial dysfunction, fibrosis, and vascular aging, emphasizing their roles in disease progression within the kidneys, heart, and lungs, where lncRNA-mediated vascular changes play a significant role in disease progression. Understanding the interactions between lncRNAs, vascular senescence, and microvascular remodeling offers promising avenues for developing targeted therapeutic strategies to mitigate the impact of aging on vascular health.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1238-H1252"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968053","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":"The vulnerable preterm heart: tale from the two chambers.","authors":"Bradley A Ruple, Jonah M Simmons, Robert I Liem, Kanokwan Bunsawat","doi":"10.1152/ajpheart.00254.2025","DOIUrl":"10.1152/ajpheart.00254.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1176-H1178"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061945","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":"Sex-specific cardiac electrophysiological remodeling influences the susceptibility to arrhythmias in elderly rats.","authors":"Rosario Statello, Giovanna Pelà, Roberta Maestri, Fabio Leonardi, Aderville Cabassi, Ignazio Verzicco, Alessandra Rossi, Luca Carnevali, Paolo Pastori, Domenico Corradi, Michele Miragoli, Emilio Macchi, Stefano Rossi","doi":"10.1152/ajpheart.00199.2025","DOIUrl":"10.1152/ajpheart.00199.2025","url":null,"abstract":"<p><p>Advanced age is a well-known risk factor for cardiovascular disease (CVD), with sex differences contributing significantly to age-dependent clinical heterogeneity. The incidence of CVD increases with age in both sexes, although men and women are predisposed toward different CVDs. However, the sex-specific arrhythmogenic alterations in aged individuals are still not described in depth. The present work aimed to analyze gross anatomical and relevant cardiac electrophysiological parameters in vivo in aged female and male rats, emphasizing sex-related disparities and their relationship with enhanced arrhythmia vulnerability. Studies were performed on healthy wild-type Groningen rats: 13 adult males (8.2 ± 1.2 mo), 13 aged males (25.6 ± 0.7 mo), 13 adult females (9.8 ± 3.2 mo), and 13 aged females (23.0 ± 1.4 mo). The adult female heart was hypertrophic compared with adult males, but aging was associated with cardiac hypertrophy only in male rats. Adult female rats had longer effective refractory period and QTc than males, but only male rats showed a significant increase in these parameters with age. Conversely, aged animals showed longer ventricular activation time than adults in both sexes. Although conduction velocity remained consistent across groups, phase map study during programmed electrical stimulation revealed prolonged activation time in the aged female compared with all other groups. Notably, although aged rats were more prone to spontaneous supraventricular extrasystoles, only aged males were more susceptible to spontaneous ventricular arrhythmias. In conclusion, sex strongly influences the cardiac electrical remodeling, with male who could experience more significant adaptations. Accordingly, when the heart is exposed to proarrhythmic stimuli, the susceptibility to arrhythmias differs between elderly males and females.<b>NEW & NOTEWORTHY</b> Aged heart is more prone to develop cardiovascular diseases including arrhythmias. The age-related electrical remodeling of the heart results in specific electrophysiological alterations in male and female rats. Males could experience more challenging adaptations as they age. They show prolongations of atrial and ventricular activation, ventricular repolarization, and refractoriness. Aged females display alterations in ventricular activation. Arrhythmias are more likely to occur in aged animals with males being more susceptible to spontaneous and induced arrhythmias.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1361-H1373"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952338","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":"Temporal mineralocorticoid receptor activation regulates the molecular clock and transcription of cardiovascular disease modulators in myeloid cells.","authors":"Seamus Heanue, Monica Kanki, James Morgan, Judy Ng, Timothy J Cole, Graeme Lancaster, David W Ray, Morag J Young","doi":"10.1152/ajpheart.00415.2024","DOIUrl":"10.1152/ajpheart.00415.2024","url":null,"abstract":"<p><p>Inappropriate mineralocorticoid receptor (MR) activation in monocytes/macrophages promotes cardiac inflammation and fibrosis. However, the specific pathways whereby the MR regulates macrophage phenotype are not fully defined. We recently identified bidirectional regulation of the MR and the molecular circadian clock in cardiac cells. Given that immune cells are important regulators of cardiac pathology, we investigated whether MR regulates the molecular circadian clock and time of day expression of inflammatory mediators in splenic monocytes/macrophages using myeloid MR null mice (MyMRKO). RNAseq and real-time quantitative PCR (RT-qPCR) analysis of whole spleen from floxed control (FC) or MyMRKO revealed differential expression of clock genes <i>Per2</i>, <i>Cry1</i>, <i>REV-ERBα</i>, and <i>DBP</i> at (Zeitgeber time) ZT0 versus ZT12. Time-of-day regulation of numerous gene targets was also disordered in MyMRKO spleen versus FC including <i>iNOS2</i>, <i>CXCR4</i>, <i>FABP3</i>, <i>S100A8</i> and <i>S100A9</i>, and <i>FGF1</i>. Aldosterone induction of <i>REV-ERBα</i>, <i>Cry1</i>, <i>iNOS</i>, <i>IL-1β</i>, <i>Arg-1</i>, <i>IL-10</i>, <i>CCL2</i>, and <i>Spp1</i> was greater when delivered at ZT0 versus ZT12, when corticosterone levels are low. Moreover, oscillating expressions of <i>Per2</i>, <i>REV-ERBα</i>, and other clock components were regulated by 10 nM aldosterone or corticosterone in immortalized bone marrow-derived cells, supporting a direct role for MR modulation of cellular clock time. Significant differences observed between male and female samples underscore the role of sex in the modulation of circadian signaling and MR-dependent pro-inflammatory phenotype in myeloid cells. Cardiac macrophage-specific bulk RNAseq and scRNAseq datasets verified MR-dependent regulation of many temporally induced genes in immune cell subsets, whereas FACS analysis showed that immune cell populations were mostly unchanged, and that <i>IL-1β</i> expression is highest in myeloid cells consistent with MyMRKO regulating <i>IL-1β</i> in this population. Our findings demonstrate the dynamic influence of MR transcriptional control of circadian clock and inflammatory pathways in myeloid cells, highlighting potential sex-based differences and offering insights into potential mechanisms underpinning MR modulation of myeloid cell phenotype.<b>NEW & NOTEWORTHY</b> Mineralocorticoid receptor (MR) signaling dynamically regulates the circadian clock and inflammatory gene expression in myeloid cells. Using myeloid-specific MR knockout mice, we identified disrupted time-of-day expression of core clock and inflammatory genes, with sex-based differences in response. These findings reveal novel MR-circadian clock interactions in immune cells and suggest a time- and sex-dependent mechanism by which MR shapes macrophage phenotype and potentially cardiac inflammation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1318-H1332"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958548","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}