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

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Prognostic circulatory signature metabolites of stable versus unstable angina: an application of NMR spectroscopy. 稳定性和不稳定性心绞痛的预后循环特征代谢物:核磁共振波谱的应用。
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-02-25 DOI: 10.1152/ajpheart.00707.2024
Ashish Gupta, Shiridhar Kashyap, Deepak Kumar, Khushbhu Meena, Anupam Kumar, Ankit Kumar Sahu, Sudeep Kumar, Aditya Kapoor
{"title":"Prognostic circulatory signature metabolites of stable versus unstable angina: an application of NMR spectroscopy.","authors":"Ashish Gupta, Shiridhar Kashyap, Deepak Kumar, Khushbhu Meena, Anupam Kumar, Ankit Kumar Sahu, Sudeep Kumar, Aditya Kapoor","doi":"10.1152/ajpheart.00707.2024","DOIUrl":"10.1152/ajpheart.00707.2024","url":null,"abstract":"<p><p>In spite of the ongoing efforts to probe the metabolic signatures of stable (SA) from unstable (UA) angina, it is concerning that to date there are no clinically validated circulatory biochemical signatures against the intrinsic anatomical changes that are screened by invasive coronary angiography. Hence, the aim of this study is to generate precise biochemical fingerprints using filtered serum-based metabolomics and high-throughput nuclear magnetic resonance (NMR) spectroscopy to accurately distinguish the metabolic signatures of patients suffering with SA or UA angina. The study includes 118 filtered serum samples from patients suffering from UA (<i>n</i> = 50) and SA (<i>n</i> = 68). High-resolution NMR spectroscopy was used to assess the metabolic remodeling in these cohorts. Subsequently, principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), and artificial neural network (ANN) analysis were adapted to engender a precise prediction model. Analysis of the receiver operating characteristic (ROC) curve was conducted to determine the clinical usefulness of metabolic markers. The outcome revealed that the metabolic profile for the underlying disease is characterized by altered metabolite levels in UA relative to SA. Creatinine, 3-OH butyrate, and aspartate level could differentiate 100% of UA from SA with 100% sensitivity and specificity. To monitor and determine UA from patients with SA, <sup>1</sup>H NMR-based filtered serum metabolic profiling seems to be a promising, less invasive, and faster investigative approach.<b>NEW & NOTEWORTHY</b> There are no metabolic signatures present to identify unstable from stable angina. Coronary angiography identifies anatomical changes after the event of unstable angina, but NMR-based metabolomics identifies unstable from stable angina within 4 h. Creatinine, 3-OH butyrate, and aspartate were able to segregate unstable from stable angina.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H761-H773"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490384","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}
引用次数: 0
Effect of 12-wk dietary nitrate supplementation on carotid arterial stiffness in postmenopausal females. 12周膳食补充硝酸盐对绝经后女性颈动脉僵硬度的影响。
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-03-11 DOI: 10.1152/ajpheart.00065.2025
Vivian Dos Santos Pinheiro, David N Proctor, Rogerio Nogueira Soares, Thiago Silveira Alvares
{"title":"Effect of 12-wk dietary nitrate supplementation on carotid arterial stiffness in postmenopausal females.","authors":"Vivian Dos Santos Pinheiro, David N Proctor, Rogerio Nogueira Soares, Thiago Silveira Alvares","doi":"10.1152/ajpheart.00065.2025","DOIUrl":"10.1152/ajpheart.00065.2025","url":null,"abstract":"<p><p>Menopause is associated with reduced nitric oxide (NO) bioavailability, a key contributor to increased arterial stiffness and, consequently, greater risk of cardiovascular disease-related mortality in postmenopausal females. Even though dietary nitrate has been shown to increase NO bioavailability in postmenopausal females acutely, previous studies showed no impact of dietary nitrate supplementation on arterial stiffness in postmenopausal females. Their findings were likely limited by the acute and/or short-term design. Thus, this study aimed to determine whether 12 wk of dietary nitrate supplementation via beetroot extract improves carotid artery stiffness in postmenopausal females. A randomized, double-blind, placebo-controlled, and parallel-design trial was conducted with 20 postmenopausal females (60-85 yr). Participants received nitrate-rich (NR-BEETx, 8.8 mmol/day) or nitrate-depleted (ND-BEETx) beetroot extract. Carotid stiffness parameters-pulse wave velocity (PWVβ), β stiffness, pressure-strain elastic modulus, augmentation index (AIx), and arterial compliance-were measured at baseline and <i>weeks 4</i>, <i>8</i>, and <i>12</i>. Serum nitrate and nitrite concentrations and blood pressure were also assessed. Compared with ND-BEETx, NR-BEETx supplementation significantly reduced PWVβ, β stiffness, elastic modulus, and AIx at <i>weeks 4</i>, <i>8</i>, and <i>12</i>, whereas arterial compliance increased by <i>week 12</i>. Serum nitrate and nitrite concentrations were elevated five- to sixfold and 1.5- to 2-fold, respectively, in the NR-BEETx group, with peak concentrations occurring at <i>week 8</i> and showing a plateau or slight decrease at <i>week 12</i>. Blood pressure remained unchanged in both groups. Twelve weeks of nitrate-rich beetroot extract supplementation improved carotid artery stiffness and increased NO bioavailability without altering blood pressure. These findings suggest that beetroot extract supplementation can be recommended as an alternative nutritional strategy to mitigate carotid artery stiffening in postmenopausal females.<b>NEW & NOTEWORTHY</b> Postmenopausal females experience reduced nitric oxide (NO) bioavailability and elevated carotid artery stiffness, a well-established independent risk factor for end-organ damage and all-cause mortality. In this study, we demonstrate that 12 wk of dietary nitrate supplementation through beetroot extract significantly increased NO bioavailability and improved carotid artery stiffness in postmenopausal females.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H937-H944"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603554","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}
引用次数: 0
Tissue elasticity modulates cardiac pacemaker cell automaticity. 组织弹性调节心脏起搏器细胞的自动性
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-03-13 DOI: 10.1152/ajpheart.00813.2024
Young Hwan Choi, Jing Leng, Jinqi Fan, Rafael J Ramirez, Hee Cheol Cho
{"title":"Tissue elasticity modulates cardiac pacemaker cell automaticity.","authors":"Young Hwan Choi, Jing Leng, Jinqi Fan, Rafael J Ramirez, Hee Cheol Cho","doi":"10.1152/ajpheart.00813.2024","DOIUrl":"10.1152/ajpheart.00813.2024","url":null,"abstract":"<p><p>Tissue elasticity is essential to a broad spectrum of cell biology and organ function including the heart. Routine cell culture models on rigid polystyrene dishes are limited in studying the impact of tissue elasticity in distinct regions of the myocardium such as the cardiac conduction system. Gelatin, a derivative of collagen, is a simple and tunable platform for modeling tissue elasticity. We sought to study the effects of increasing tissue stiffness on cardiac pacemaker cell function by using transcription factor-reprogrammed pacemaker cells cultured on gelatin hydrogels with specific elasticity. Our data indicate that automaticity of the pacemaker cells, measured in rhythmic contractions and oscillating intracellular Ca<sup>2+</sup> transients, was enhanced when cultured on a stiffer matrix of 14 kPa. This was accompanied by increased expression of cardiac pacemaker ion channel, Hcn4, and a reciprocal decrease in Cx43 expression compared with control conditions. Propagation of Ca<sup>2+</sup> transients was slower in the pacemaker cell monolayers compared with control, which recapitulates a hallmark feature in the native pacemaker tissue. Ca<sup>2+</sup> transient propagation of pacemaker cell monolayer was slower on stiffer than on softer hydrogel, and this was dependent on enhanced proliferation of cardiac fibroblasts rather than differences in gap junctional coupling. Culturing the pacemaker cells on rigid plastic plates led to irregular or loss of synchronous contractions as well as unusually long Ca<sup>2+</sup> transient durations. Taken together, our data demonstrate that automaticity of pacemaker cells is augmented by stiffer extracellular matrix substrates within the elasticity range of the healthy myocardium. This simple approach presents a physiological in vitro model to study mechanoelectric feedback of cardiomyocytes including the conduction system cells.<b>NEW & NOTEWORTHY</b> The major achievement of this work is development of a robust and straightforward approach to model cardiac conduction system cells with a range of cardiac tissue elasticity with a goal to understand the impact of tissue stiffness on cardiac pacing. Our data provide a framework for further investigation of the heart rhythm in health and disease in the context of fibrosis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H978-H990"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623109","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}
引用次数: 0
Noncoding RNA as potential therapeutics to rescue mitochondrial dysfunction in cardiovascular diseases. 非编码 RNA 作为挽救心血管疾病线粒体功能障碍的潜在疗法
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-02-28 DOI: 10.1152/ajpheart.00774.2024
Hafsat O Alabere, Andrew D Taylor, Brianna R Miller, Remi Nohoesu, Roxy Nicoletti, Joshua Mogus, Ethan M Meadows, John M Hollander
{"title":"Noncoding RNA as potential therapeutics to rescue mitochondrial dysfunction in cardiovascular diseases.","authors":"Hafsat O Alabere, Andrew D Taylor, Brianna R Miller, Remi Nohoesu, Roxy Nicoletti, Joshua Mogus, Ethan M Meadows, John M Hollander","doi":"10.1152/ajpheart.00774.2024","DOIUrl":"10.1152/ajpheart.00774.2024","url":null,"abstract":"<p><p>Noncoding RNAs (ncRNAs) are critical regulators of mitochondrial function in cardiovascular diseases. Several studies have explored the manipulation of ncRNAs in mitochondrial dysfunction in different cardiovascular disease contexts, however, there is a dearth of information on the exploration of these noncoding RNAs as actual therapeutics to ameliorate cardiovascular diseases. This systematic review examines the roles of various ncRNAs in modulating mitochondrial dysfunction across major cardiovascular diseases and how they can be targeted to the mitochondria. A comprehensive literature search was conducted using Web of Science and Scopus databases, following the PRISMA guidelines. Original research articles in the English language, focusing on ncRNAs and mitochondrial dysfunction in specific cardiovascular diseases, were eligible for inclusion. A total of 76 studies were included in the systematic review with up to 100 ncRNAs identified as therapeutic biomarkers. The identified ncRNAs participate in regulating mitochondrial processes including oxidative phosphorylation (OXPHOS), fission/fusion dynamics, apoptosis, and calcium handling in cardiovascular diseases. Mitochondrial targeting moieties including mitochondrial targeting cell-penetrating peptides, mitochondrial targeting liposomes, and aptamers can be conjugated to ncRNAs and delivered to the heart via various injection routes including the pericardium or the myocardium. However, significant challenges remain in developing effective delivery methods to modulate these ncRNAs in vivo.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H846-H864"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522264","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}
引用次数: 0
Leveraging circulating DNase I activity to detect silent coronary artery disease among hypertensive diabetes individuals. 利用循环dna酶I活性检测高血压糖尿病患者无症状冠状动脉疾病
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-03-11 DOI: 10.1152/ajpheart.00088.2025
Amit Babu, Chinnappa A Uthaiah, Preetam Narayan Wasnik, Neha Rani Verma, Matam Vijay-Kumar, Jessy Abraham
{"title":"Leveraging circulating DNase I activity to detect silent coronary artery disease among hypertensive diabetes individuals.","authors":"Amit Babu, Chinnappa A Uthaiah, Preetam Narayan Wasnik, Neha Rani Verma, Matam Vijay-Kumar, Jessy Abraham","doi":"10.1152/ajpheart.00088.2025","DOIUrl":"10.1152/ajpheart.00088.2025","url":null,"abstract":"<p><p>In individuals with diabetic hypertension, silent coronary artery disease (CAD) is common due to underlying chronic inflammation, but there is no biomarker to monitor this high-risk group of individuals before noticeable symptoms emerge clinically. cfDNA from dying endothelial cells triggers chronic inflammation, leading us to hypothesize that enzymes that degrade cfDNA, DNase I and/or II, could serve as more sensitive biomarkers for silent CAD. To test this, we conducted a study with 30 hypertensive diabetic patients with clinical symptoms of CAD (CAD-HTN-DM) and 30 controls without CAD (HTN-DM). Negligible serum DNase II activity was detected in both groups. Student's <i>t</i> test was used to compare cfDNA, DNase I activity, and groups. We observed elevated serum DNase I activity in the CAD-HTN-DM group (1.71 ± 0.1 U/mL) compared with the HTN-DM group (1.12 ± 0.1 U/mL) (<i>P</i> < 0.0001). Among the CAD-HTN-DM group, DNase I activity was significantly higher in patients with all three coronary arteries blocked, even though the cfDNA levels were similar in both groups. Elevated DNase I activity was associated with a 1.5-fold increased risk of major adverse cardiac events despite ongoing treatment with statins, antihypertensive medications, and antidiabetic therapies. Surprisingly, serum DNase I activity was lower in patients who suffered a myocardial infarction. By leveraging our observations, we hope that regular monitoring of serum DNase I activity will identify individuals at high risk for the clinical onset of CAD, enabling early intervention to mitigate its adverse effects and slow its progression.<b>NEW & NOTEWORTHY</b> Our observation suggests that the progression of cardiac disease among hypertensive patients with diabetes is associated with elevated DNase I activity that maintains optimal cfDNA levels, thereby reducing its inflammatory potential and worsening of cardiac dysfunction. Thus, DNase I activity may be both a protective factor early on and a potential biomarker for cardiac health among hypertensive patients with diabetes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H973-H977"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603567","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}
引用次数: 0
An ovary-intact postmenopausal HFpEF mouse model; menopause is more than just estrogen deficiency. 绝经后卵巢完整的HFpEF小鼠模型;更年期不仅仅是雌激素缺乏。
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-02-18 DOI: 10.1152/ajpheart.00575.2024
Mei Methawasin, Joshua Strom, Vito A Marino, Jochen Gohlke, Julia Muldoon, Shelby R Herrick, Robbert van der Piji, John P Konhilas, Henk Granzier
{"title":"An ovary-intact postmenopausal HFpEF mouse model; menopause is more than just estrogen deficiency.","authors":"Mei Methawasin, Joshua Strom, Vito A Marino, Jochen Gohlke, Julia Muldoon, Shelby R Herrick, Robbert van der Piji, John P Konhilas, Henk Granzier","doi":"10.1152/ajpheart.00575.2024","DOIUrl":"10.1152/ajpheart.00575.2024","url":null,"abstract":"<p><p>The incidence of heart failure with preserved ejection fraction (HFpEF) in women significantly increases following menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase in prevalence among men, suggesting that menopause is a provocative event for HFpEF. However, the underlying mechanisms remain elusive and challenging to investigate in human subjects; moreover, an attempt to create HFpEF in ovariectomized (OVX) mice was unsuccessful. In this study, we created an animal model that resembles HFpEF in women undergoing natural menopause. We used 4-vinylcyclohexene dioxide (VCD) to induce \"ovary-intact\" menopause, combined with the 2hit regimen (HFpEF inducing regimen) to model postmenopausal HFpEF. The female-VCD-2hit mice demonstrate diastolic dysfunction. At the left ventricle (LV) levels, the increased stiffness coefficient of end-diastolic pressure-volume relation (EDPVR), elevated LV end-diastolic pressure, and increased relaxation time constant indicate a heightened LV stiffness, delayed relaxation, and elevated LV filling pressure. At the cardiomyocyte level, the female-VCD-2hit mice exhibit increased cellular diastolic stiffness and delayed relaxation, suggesting that the observed LV dysfunction is derived from the cardiomyocytes. In addition, plasma N-terminal pro-β-type natriuretic peptide (NT-pro-BNP) levels were elevated, whereas Xbp1s transcript levels were reduced, further supporting the existence of HFpEF. Plasma-free testosterone was increased in VCD mice compared with premenopausal and OVX models. Further studies are required to determine whether the relative increase in testosterone is the factor driving HFpEF susceptibility in VCD mice. Ovary-intact postmenopausal status makes female mice vulnerable to HFpEF development. The VCD-2hit model develops a robust HFpEF-like phenotype and is suitable for studying female HFpEF.<b>NEW & NOTEWORTHY</b> Although ovariectomized mice were observed to be resistant to developing HFpEF, ovary-intact postmenopausal mice exhibited an HFpEF-like phenotype under metabolic stress conditions. The increased susceptibility of ovary-intact postmenopausal mice may be due to relative androgen excess conditions, as postmenopausal ovaries retain the ability to secrete androgens. Menopause should be viewed as the imbalance of estrogen and androgens rather than merely an estrogen deficiency, and the role of female androgens in postmenopausal HFpEF warrants further investigation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H719-H733"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439350","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}
引用次数: 0
Mechanistic insight into the role of cardiac-enriched microRNAs in diabetic heart injury. 心脏富集microrna在糖尿病心脏损伤中的作用机制。
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-03-04 DOI: 10.1152/ajpheart.00736.2024
Branislav Kura, Lucia Kindernay, Dinender Singla, Ulrika Dulova, Monika Bartekova
{"title":"Mechanistic insight into the role of cardiac-enriched microRNAs in diabetic heart injury.","authors":"Branislav Kura, Lucia Kindernay, Dinender Singla, Ulrika Dulova, Monika Bartekova","doi":"10.1152/ajpheart.00736.2024","DOIUrl":"10.1152/ajpheart.00736.2024","url":null,"abstract":"<p><p>Cardiovascular complications, particularly diabetic cardiomyopathy (DCM), are the primary causes of morbidity and mortality among individuals with diabetes. Hyperglycemia associated with diabetes leads to cardiomyocyte hypertrophy, apoptosis, and myocardial fibrosis, culminating in heart failure (HF). Patients with diabetes face a 2-4 times greater risk of developing HF compared with those without diabetes. Consequently, there is a growing interest in exploring the molecular mechanisms that contribute to the development of DCM. MicroRNAs (miRNAs) are short, single-stranded, noncoding RNA molecules that participate in the maintenance of physiological homeostasis through the regulation of essential processes such as metabolism, cell proliferation, and apoptosis. At the posttranscriptional level, miRNAs modulate gene expression by binding directly to genes' mRNAs. Multiple cardiac-enriched miRNAs were reported to be dysregulated under diabetic conditions. Different studies revealed the role of specific miRNAs in the pathogenesis of diabetes and related cardiovascular complications, including cardiomyocyte hypertrophy and fibrosis, mitochondrial dysfunction, metabolic impairment, inflammatory response, or cardiomyocyte death. Circulating miRNAs have been shown to represent the potential biomarkers for early detection of diabetic heart injury. A deeper understanding of miRNAs and their role in diabetes-related pathophysiological processes could lead to new therapeutic strategies for addressing cardiac complications associated with diabetes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H865-H884"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539849","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}
引用次数: 0
Whole genome transcriptomics reveal distinct atrial versus ventricular responses to neonatal hyperoxia. 全基因组转录组学揭示了新生儿高氧时心房和心室的不同反应。
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-03-06 DOI: 10.1152/ajpheart.00039.2025
E David Cohen, Min Yee, Kyle Roethlin, Irina Prelipcean, Eric M Small, George A Porter, Michael A O'Reilly
{"title":"Whole genome transcriptomics reveal distinct atrial versus ventricular responses to neonatal hyperoxia.","authors":"E David Cohen, Min Yee, Kyle Roethlin, Irina Prelipcean, Eric M Small, George A Porter, Michael A O'Reilly","doi":"10.1152/ajpheart.00039.2025","DOIUrl":"10.1152/ajpheart.00039.2025","url":null,"abstract":"<p><p>Preterm infants exposed to supplemental oxygen (hyperoxia) are at risk for developing heart failure later in life. Exposing rodents in early postnatal life to hyperoxia causes heart failure that resembles cardiac disease seen in adult humans who were born preterm. Neonatal hyperoxia exposure affects the left atrium and left ventricle differently, inhibiting the proliferation and survival of atrial cardiomyocytes while enhancing cardiomyocyte differentiation in the ventricle. In this study, whole genome transcriptomics revealed the left atria of neonatal mice are more responsive to hyperoxia than the left ventricle, with the expression of 4,285 genes affected in the atrium and 1,743 in the ventricle. Although hyperoxia activated p53 target genes in both chambers, it caused greater DNA damage, phosphorylation of the DNA damage responsive ataxia-telangiectasia mutated (ATM) kinase, mitochondrial stress, and apoptosis in the atrium. In contrast, hyperoxia induced the expression of genes involved in DNA repair and stress granules in the ventricle. Atrial cells also showed a greater loss of extracellular matrix and superoxide dismutase 3 (SOD3) expression, possibly contributing to the enlargement of the left atrium and reduced velocity of blood flow across the mitral valve seen in mice exposed to hyperoxia. Diastolic dysfunction and heart failure in hyperoxia-exposed mice may thus stem from its effects on the left atrium, suggesting chamber-specific therapies may be needed to address diastolic dysfunction and heart failure in people who were born preterm.<b>NEW & NOTEWORTHY</b> Preterm infants often require oxygen (hyperoxia) at birth, but early exposure increases the risk of heart failure later in life. Previously, we showed neonatal mice exposed to hyperoxia develop adult diastolic dysfunction and heart failure like preterm-born humans. In this study, RNA-sequencing reveals hyperoxia induces broader transcriptional changes in the atrium than ventricle, including upregulation of stress pathways and loss of superoxide dismutase 3 and extracellular matrix genes, highlighting the atrium's heightened vulnerability to hyperoxia.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H832-H845"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565579","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}
引用次数: 0
Role of shear stress-induced red blood cell released ATP in atherosclerosis. 剪切应力诱导红细胞释放ATP在动脉粥样硬化中的作用。
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-02-21 DOI: 10.1152/ajpheart.00875.2024
Yunpei Zhang, Haoyu Sun, Aayush Gandhi, Yong Du, Saman Ebrahimi, Yanyan Jiang, Sulei Xu, Hope Uwase, Alane Seidel, Sarah S Bingaman, Amy C Arnold, Christian Nguyen, Wei Ding, Matthew D Woolard, Ryan Hobbs, Prosenjit Bagchi, Pingnian He
{"title":"Role of shear stress-induced red blood cell released ATP in atherosclerosis.","authors":"Yunpei Zhang, Haoyu Sun, Aayush Gandhi, Yong Du, Saman Ebrahimi, Yanyan Jiang, Sulei Xu, Hope Uwase, Alane Seidel, Sarah S Bingaman, Amy C Arnold, Christian Nguyen, Wei Ding, Matthew D Woolard, Ryan Hobbs, Prosenjit Bagchi, Pingnian He","doi":"10.1152/ajpheart.00875.2024","DOIUrl":"10.1152/ajpheart.00875.2024","url":null,"abstract":"<p><p>Altered hemodynamics is a key factor for atherosclerosis. For decades, endothelial cell (EC) responses to fluid-generated wall shear stress have been the central focus for atherogenesis. However, circulating blood is not a cell-free fluid, it contains mechanosensitive red blood cells (RBCs) that are also subjected to altered hemodynamics and release a large amount of ATP, but their impact on atherosclerosis has been overlooked. The focus of this study is the role of shear stress (SS)-induced RBC-released ATP in atherosclerosis. Hypercholesterolemic mouse models with and without RBC-Pannexin 1 deletion were used for the study. Results showed that SS-induced release of ATP from RBCs was at µM concentrations, three-orders of magnitude higher than that from other cell types. Suppression of RBC-released ATP via deletion of Pannexin 1, a mechanosensitive ATP-permeable channel, reduced high-fat diet-induced aortic plaque burden by 40%-60%. Importantly, the location and the extent of aortic atherosclerotic lesions spatially matched with the ATP deposition profile at aortic wall predicted by a computational fluid dynamic (CFD) model. Furthermore, hypercholesterolemia increases EC susceptibility to ATP with potentiated increase in [Ca<sup>2+</sup>]<sub>i</sub>, an initial signaling for aortic EC barrier dysfunction, and an essential cause for lipid accumulation and inflammatory cell infiltration. The computational prediction also provides a physics-based explanation for RBC-released ATP-induced sex disparities in atherosclerosis. Our study reveals an important role of RBC-released ATP in the initiation and progression of atherosclerosis. These novel findings provide a more comprehensive view of how altered hemodynamics and systemic risk factors synergistically contribute to atherosclerosis.<b>NEW & NOTEWORTHY</b> This study reveals that, in addition to fluid-derived wall shear stress, the disturbed blood flow-induced release of ATP from mechanosensitive red blood cells (RBCs), the major cellular components of blood, along with hypercholesterolemia-induced increases in endothelial cell susceptibility to ATP contribute significantly to the initiation and progression of atherosclerosis. These novel findings advance our current understanding of how altered hemodynamics and hypercholesterolemia synergistically contribute to atherosclerosis for the first time with the inclusion of RBCs.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H774-H791"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466655","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}
引用次数: 0
From signal to action: the roles of β1-adrenergic receptors in cardiac function and disease. 从信号到作用:β1-肾上腺素能受体在心功能和疾病中的作用。
IF 4.1 2区 医学
American journal of physiology. Heart and circulatory physiology Pub Date : 2025-04-01 Epub Date: 2025-03-10 DOI: 10.1152/ajpheart.00151.2025
W Glen Pyle
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引用次数: 0
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