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

{"title":"Heart and health behavior responses to GLP-1 receptor agonists: a 12-wk study using wearable technology and causal inference.","authors":"Gregory J Grosicki, Jeongeun Kim, Finn Fielding, Summer R Jasinski, Christopher Chapman, William von Hippel, Kristen E Holmes","doi":"10.1152/ajpheart.00809.2024","DOIUrl":"10.1152/ajpheart.00809.2024","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed for the treatment of type 2 diabetes but have recently been approved for chronic weight management and reducing cardiovascular risk in individuals with overweight and obesity. Despite this approval, significant heterogeneity in the cardioprotective benefits and less desirable increases in resting heart rate (RHR) with GLP-1 RAs have been reported. To better understand cardiovascular responses to GLP-1 RAs and the potential role of health behaviors in influencing these responses, we leveraged wearable technology and causal inference analysis. We tracked RHR, heart rate variability (HRV), physical activity, and sleep in 66 individuals (42 ± 9 yr, body mass index: 30.0 ± 7 kg/m²) from the week before to 12 wk following the initiation of GLP-1 RA medication. Propensity score matching on a larger sample of wearable users identified a control group with similar anthropometric and cardiovascular characteristics (<i>P</i>s > 0.26). After the 12-wk study period, GLP-1 users showed significant (<i>P</i>s < 0.05) weight loss (-10.0%, 95% CI: -11.2% to -8.5%) and changes in RHR (3.2 ± 0.8 beats/min) that were mediated (<i>P</i> < 0.01) by changes in HRV (-6.2 ± 1.4 ms) compared with control. Trends (<i>P</i>s < 0.10) suggested that increases in weekly physical activity were associated with GLP-1 RA medication (31.5 ± 13.2 min) and that higher physical activity levels accompanied an attenuation of RHR increases. Our real-world findings align with clinical trial data in showing rapid and significant weight loss with GLP-1 RAs, coinciding with increases in RHR that are mediated by changes in autonomic function (i.e., HRV). Physical activity may help to offset RHR increases, but further research is needed to confirm these effects.<b>NEW & NOTEWORTHY</b> These findings are among the first to provide daily insights into cardiovascular and behavioral responses following GLP-1 RA initiation. Substantial weight loss and significant increases in resting heart rate mediated by reductions in heart rate variability during the initial 12 wk of GLP-1 RA therapy were observed. In addition, trends suggest an increase in physical activity with GLP-1 therapy, and that physical activity may help to temper GLP-1 RA-associated increases in resting heart rate.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H235-H241"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869287","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":"Lab-grown, 3D extracellular matrix particles improve cardiac function and morphology in myocardial ischemia.","authors":"Mark Broadwin, Katerina St Angelo, Max Petersen, Rayane B Teixeira, Dwight D Harris, Christopher R Stone, Cynthia Xu, Meghamsh Kanuparthy, Frank W Sellke, Jeffrey Morgan, M Ruhul Abid","doi":"10.1152/ajpheart.00581.2024","DOIUrl":"10.1152/ajpheart.00581.2024","url":null,"abstract":"<p><p>The promise of injection of extracellular matrix (ECM) from animal hearts as a treatment of myocardial ischemia has been limited by immune reactions and harsh ECM-damaging extraction procedures. We developed a novel method to produce lab-grown human three-dimensional (3-D) acellular ECM particles from human mesenchymal stem cells (MSCs) to mitigate product variability, immunogenicity, and preserve ECM architecture. We hypothesized that intramyocardial injection (I/M) of this novel ECM (dia ∼ 200 microns) would improve cardiac function in a postmyocardial infarction (MI) murine model. WT mice aged 8-10 wk underwent ligation of the left anterior descending coronary (LAD) artery and I/M injection of 10 μL ECM or normal saline (<i>n</i> = 10/group). Compared with control, ECM-treated hearts showed significant reduction in infarct size (<i>P</i> = 0.04), increased capillary density in ischemic myocardium (<i>P</i> = 0.01), and increased fractional shortening (FS) (<i>P</i> < 0.05) on <i>postoperative days</i> (POD) <i>14</i>, <i>21</i>, and <i>28</i> by echocardiography. There were no significant differences in immunogenic response as determined by TNFα, IL6, CD86, or CD163 levels (<i>P</i> > 0.05 for all) in the hearts. Biodistribution of fluorophore-conjugated ECM demonstrated localized epifluorescence in the heart after I/M injection, without significant peripheral end organ epifluorescence. Proteomic analysis of ischemic and perfused myocardium from control and ECM-treated hearts using LC-MS/MS (<i>n</i> = 3/group) detected significant changes in proteins involved in cardiomyocyte contractility and fatty acid metabolism. These findings suggest that 3-D ECM particles induce recovery of ischemic myocardium, by upregulating protein networks involved in cellular contractility and metabolism. Taken together, 3-D ECM particles represent a promising therapy for MI and warrant confirmatory studies in a high-fidelity large animal model.<b>NEW & NOTEWORTHY</b> Our novel lab-grown, human 3-D extracellular matrix (ECM) represents a novel therapeutic approach to prevent pathological remodeling and heart failure in an animal model of heart attack. This novel finding may help develop nonsurgical therapeutic modalities aimed at reducing the global burden of cardiovascular disease.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H221-H234"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869288","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":"A minimally invasive swine model of chronic kidney disease-associated heart failure.","authors":"Spyros A Mavropoulos, Tadao Aikawa, Renata Mazurek, Tomoki Sakata, Kelly Yamada, Kenji Watanabe, Genya Sunagawa, Samta Veera, Deanndria T Singleton, Kyra Leonard, Taro Kariya, Susmita Sahoo, Kiyotake Ishikawa","doi":"10.1152/ajpheart.00449.2024","DOIUrl":"10.1152/ajpheart.00449.2024","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is on the rise, and over 50% of patients die from cardiac causes. Patients develop heart failure due to unelucidated reno-cardiac interactions, termed type 4 cardiorenal syndrome (CRS4). The aim of this study is to establish and characterize a reliable model of CRS4 in swine with marked cardiac diastolic dysfunction. Yorkshire pigs (19.9 ± 1.7 kg, 4 females and 5 males) underwent staged renal artery embolization using autologous clot. Echocardiogram, aortic pressure (AoP), renal angiogram, and blood samples were assessed monthly. At 4 mo, animals were euthanized after measuring glomerular filtration rate (GFR) and left ventricular (LV) pressure-volume parameters. Heart and kidneys were collected for postmortem analyses. Size-matched swine (<i>n</i> = 5; 43.7 ± 9.8 kg) served as controls. After three dose-titrated renal embolization, serum creatinine (SCr) and AoP increased by wk 10. At 4 mo, SCr (2.03 ± 0.45 vs. 1.34 ± 0.17 mg/dL, <i>P</i> = 0.013) and AoP (158 ± 16 vs. 121 ± 8 mmHg, <i>P</i> = 0.001) were higher, and GFR was lower (12 ± 3 vs. 131 ± 7 mL/min, <i>P</i> < 0.001) than size-matched controls. Although the LV ejection fraction was similar, the slope of the end-diastolic pressure-volume relationship was steeper in pigs after renal embolization (0.36 ± 0.09 vs. 0.17 ± 0.06, <i>P</i> = 0.003), indicating increased LV stiffness. LV mass index (2.73 ± 0.19 vs. 2.50 ± 0.13 g/kg, <i>P</i> = 0.043) and wall-thickness (11.4 ± 0.8 vs. 8.9 ± 1.2 mm, <i>P</i> = 0.003) increased. These were accompanied by histologically increased fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction. Repeat titrated renal embolization resulted in a model that exhibits advanced CKD and cardiac abnormalities consistent with CRS4.<b>NEW & NOTEWORTHY</b> Cardiac pathological changes consistent with heart failure with preserved ejection fraction can be induced in a large animal model by serial and titrated renal embolization of kidneys with autologous clot, leading to severe renal dysfunction and impaired cardiac diastolic function.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H260-H270"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880877","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":"Hemodynamic response of the aortic valve during dobutamine onset then progressive aortic banding.","authors":"Rob Eerdekens, Philipos K Gebremedhin, Daniel T Johnson, Richard L Kirkeeide, Gretchen L Howe, Richard W Smalling, K Lance Gould, Pim A L Tonino, Nils P Johnson","doi":"10.1152/ajpheart.00616.2024","DOIUrl":"10.1152/ajpheart.00616.2024","url":null,"abstract":"<p><p>An increasing number of procedures over the past two decades for aortic stenosis (AS) reflects the combination of an aging population and less invasive transcatheter options. As a result, the hemodynamics of the aortic valve (AV) have gained renewed interest to understand its behavior and to optimize patient selection. We studied the hemodynamic relationship between pressure loss (ΔP) and transvalvular flow (Q) of the normal AV as well as the impact of a variable supravalvular stenosis. Our mechanistic study included 11 healthy swine monitored during dobutamine stress and followed by acute aortic banding to simulate AS. Hemodynamics were continuously recorded, and transvalvular ΔP versus Q were analyzed using proportional and linear models. During dobutamine infusion, normal valves exhibited a highly linear relationship between ΔP and Q (median <i>R</i>² of 0.93). Progressive aortic banding eventually displayed a highly linear relationship between an increasing ΔP and the decreasing Q, characterized by a constant systemic circulatory resistance (median <i>R</i>² of 0.91). Consequently, a normal AV can be described by a single parameter: its resistance, median 0.37 Wood units (WU) in swine. During dobutamine stress and aortic banding, the systemic bed behaves like a constant and stable resistance, median of 11.9 WU in swine. These findings carry significant implications for quantifying normal and diseased AV behavior and potentially might improve patient selection and treatment outcomes.<b>NEW & NOTEWORTHY</b> This study demonstrates that the normal aortic valve functions like a resistor with a proportional pressure loss ΔP versus transvalvular flow Q relationship. During dobutamine stress and progressive aortic banding, a \"load line\" of constant resistance characterizes the systemic circulation. Consequently, during stress conditions, the relative pressure loss over a stenotic aortic valve (the stress aortic valve index, SAVI) quantifies the relative reduction in maximal flow. Potentially, SAVI might optimize patient selection for procedures to treat aortic stenosis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H377-H385"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982494","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":"A heavy burden: unraveling the consequences of perinatal iron deficiency on offspring heart health.","authors":"Jennifer J Gardner, Jessica L Bradshaw","doi":"10.1152/ajpheart.00860.2024","DOIUrl":"10.1152/ajpheart.00860.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H242-H244"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880876","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":"Endothelial cell-selective adhesion molecule deficiency exhibits increased pulmonary vascular resistance due to impaired endothelial nitric oxide signaling.","authors":"Vadym Buncha, Liwei Lang, Katie Anne Fopiano, Daria V Ilatovskaya, Gaston Kapuku, Alexander D Verin, Zsolt Bagi","doi":"10.1152/ajpheart.00593.2024","DOIUrl":"10.1152/ajpheart.00593.2024","url":null,"abstract":"<p><p>Endothelial cell-selective adhesion molecule (ESAM) is a member of tight junction molecules, highly abundant in the heart and the lung, and plays a role in regulating endothelial cell permeability. We previously reported that mice with genetic ESAM deficiency (<i>ESAM</i>^-/-) exhibit coronary microvascular dysfunction leading to the development of left ventricular diastolic dysfunction. Here, we hypothesize that <i>ESAM</i>^-/- mice display impairments in the pulmonary vasculature, affecting the overall pulmonary vascular resistance (PVR). We utilized <i>ESAM</i>^-/- mice and employed isolated, ventilated, and perfused whole lung preparation to assess PVR independently of cardiac function. PVR was assessed in response to stepwise increases in flow, and also in response to perfusion of the endothelium-dependent agonist, bradykinin, the thromboxane analog, U46619, and the nitric oxide (NO) donor sodium nitroprusside (SNP). We found that PVR, at every applied flow rate, is significantly elevated in <i>ESAM</i>^-/- mice compared with WT mice. Bradykinin-induced reduction in PVR and U46619-induced increase in PVR were both diminished in <i>ESAM</i>^-/- mice, whereas SNP-induced responses were similar in wild-type (WT) and <i>ESAM</i>^-/- mice. Inhibition of NO synthase with <i>N</i>(ω)-nitro-l-arginine methyl ester increased agonist-induced PVR in WT but not in <i>ESAM</i>^-/- mice. Pulmonary arteries isolated from <i>ESAM</i>^-/- mice exhibited a reduced level of phospho-Ser473-Akt and phospho-Ser1177-eNOS. Furthermore, in human lung microvascular endothelial cells cultured under flow conditions, we found that siRNA-mediated knockdown of ESAM impaired fluid shear stress-induced endothelial cell alignment. Thus, we suggest that ESAM plays an important role in the endothelium-dependent, flow/shear stress- and vasoactive agonist-stimulated, and NO-mediated maintenance of PVR in mice.<b>NEW & NOTEWORTHY</b> Our study reveals a novel role for ESAM in contributing to the maintenance of pulmonary vascular resistance under normal physiological conditions. Employing mice with global genetic deficiency of ESAM and using isolated whole lung preparation, we show significant impairments in nitric oxide-mediated pulmonary artery function. In vitro cell culture studies demonstrate impaired fluid shear stress-induced cell alignment in human lung endothelial cells after siRNA-mediated ESAM knockdown.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H283-H293"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909017","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":"G protein regulation by RGS proteins in the pathophysiology of dilated cardiomyopathy.","authors":"Yadhira E Garcia, Benita Sjögren, Patrick Osei-Owusu","doi":"10.1152/ajpheart.00653.2024","DOIUrl":"10.1152/ajpheart.00653.2024","url":null,"abstract":"<p><p>Regulators of G protein signaling (RGS) proteins fine-tune signaling via heterotrimeric G proteins to maintain physiologic homeostasis in various organ systems of the human body including the brain, kidney, heart, and vasculature. Impaired regulation of G protein signaling by RGS proteins is implicated in the pathogenesis of several human diseases including various forms of cardiomyopathy such as hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Both genetic and nongenetic changes that impinge on G protein signaling in cardiomyocytes are implicated in the etiology of DCM, and there is accumulating evidence that such genetic and nongenetic changes affecting G protein signaling in cell types other than cardiomyocytes could serve as a DCM trigger in humans. This review discusses and highlights mammalian RGS proteins and their roles in cardiac physiology and disease, with a specific focus on the current understanding of the etiology of DCM and the pathogenic roles of RGS proteins that are prominently expressed in the cardiovascular system. Growing evidence suggests that defects in G protein regulation by RGS proteins in the cardiovascular system likely contribute to cardiomyocyte structural damage and decreased contractile function that hallmark DCM. Further studies that enhance the understanding of the dynamics of G protein regulation by RGS proteins in several cell types in the myocardium and the vasculature are critical to gaining more insight into the etiology of DCM and heart failure, and to the identification of novel therapeutic targets.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H348-H360"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942651","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":"Development of a framework for the hemodynamic impact of positive end-expiratory pressure in normal and heart failure conditions.","authors":"Takuya Nishikawa, Kazunori Uemura, Hiroki Matsushita, Hidetaka Morita, Kei Sato, Yuki Yoshida, Masafumi Fukumitsu, Toru Kawada, Keita Saku","doi":"10.1152/ajpheart.00414.2024","DOIUrl":"10.1152/ajpheart.00414.2024","url":null,"abstract":"<p><p>Positive end-expiratory pressure (PEEP) improves respiratory conditions. However, the complex interaction between PEEP and hemodynamics in patients with heart failure makes it challenging to determine appropriate PEEP settings. In this study, we developed a framework for the impact of PEEP on hemodynamics considering cardiac function, by integrating the impact of PEEP in the generalized circulatory equilibrium framework, and validated the framework by assessing its ability to accurately predict PEEP-induced hemodynamics. In eight dogs, PEEP was increased stepwise, and hemodynamic responses were measured under normal, volume-loaded, and myocardial infarction (MI)-induced heart failure conditions. For predicting hemodynamics under PEEP using the proposed framework, the PEEP-intrathoracic pressure (ITP) relationship was empirically established in dogs. Hemodynamic parameters were estimated at each PEEP level based on the hemodynamics recorded without PEEP. The parameters were then used to predict hemodynamics under various heart conditions. The predicted and measured values were compared. A stepwise increase in PEEP decreased arterial pressure (AP) and cardiac output (CO). Left atrial pressure (LAP) decreased in normal hearts but increased in MI hearts. Predicted AP [<i>R</i>², 0.92; root mean-squared error (RMSE), 6.3 mmHg], CO (<i>R</i>², 0.96; RMSE, 7.9 mL·min^-1·kg^-1), and LAP (<i>R</i>², 0.92; RMSE, 2.3 mmHg) matched measured values with high accuracy, irrespective of volume status or heart condition. In conclusion, we developed a framework for the hemodynamic impact of PEEP considering cardiac function and demonstrated its validity. The results indicate that the effects of PEEP on hemodynamics can be explained primarily by ITP and are modulated by cardiac function.<b>NEW & NOTEWORTHY</b> Positive end-expiratory pressure (PEEP) has both the benefit of improving respiratory status and the disadvantage of deteriorating hemodynamics. As the effects of PEEP vary depending on cardiac function, optimizing PEEP setting remains challenging. This study is the first to systematically elucidate the impact of PEEP on hemodynamics with consideration of cardiac function and establish a validated framework. This novel framework provides a comprehensive understanding of the hemodynamic effects of PEEP.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H361-H376"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982365","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":"Ceramide toxicity in cardiomyocytes: from Farber disease to cardiovascular diseases.","authors":"Lindsey A Fitzsimons, Harilaos Filippakis","doi":"10.1152/ajpheart.00843.2024","DOIUrl":"10.1152/ajpheart.00843.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H323-H326"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869286","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":"BRD4 inhibition rewires cardiac macrophages toward a protective phenotype marked by low MHC class II expression.","authors":"Katherine B Schuetze, Matthew S Stratton, Rushita A Bagchi, Alexander R H Hobby, Marina B Felisbino, Marcello Rubino, Lee S Toni, Caroline Reges, Maria A Cavasin, Rachel H McMahan, Michael Alexanian, Ronald J Vagnozzi, Timothy A McKinsey","doi":"10.1152/ajpheart.00438.2024","DOIUrl":"10.1152/ajpheart.00438.2024","url":null,"abstract":"<p><p>Bromodomain and extraterminal domain (BET) proteins, including BRD4, bind acetylated chromatin and coactivate gene transcription. A BET inhibitor, JQ1, prevents and reverses pathological cardiac remodeling in preclinical models of heart failure. However, the underlying cellular mechanisms by which JQ1 improves cardiac structure and function remain poorly defined. Here, we demonstrate that BRD4 knockdown reduced expression of genes encoding CC chemokines in cardiac fibroblasts, suggesting a role for this epigenetic reader in controlling fibroblast-immune cell cross talk. Consistent with this, JQ1 dramatically suppressed recruitment of monocytes to the heart in response to stress. Normal mouse hearts were found to have approximately equivalent numbers of major histocompatibility complex (MHC-II)^high and MHC-II^low resident macrophages, whereas MHC-II^low macrophages predominated following JQ1 treatment. Single-cell RNA-seq data confirmed that JQ1 treatment or BRD4 knockout in CX3CR1⁺ cells reduced MHC-II gene expression in cardiac macrophages, and studies with cultured macrophages further illustrated a cell autonomous role for BET proteins in controlling the MHC-II axis. Bulk RNA-seq analysis demonstrated that JQ1 blocked pro-inflammatory macrophage gene expression through a mechanism that likely involves repression of NF-κB signaling. JQ1 treatment reduced cardiac infarct size in mice subjected to ischemia/reperfusion. Our findings illustrate that BET inhibition affords a powerful pharmacological approach to manipulate monocyte-derived and resident macrophages in the heart. Such an approach has the potential to enhance the reparative phenotype of macrophages to promote wound healing and limit infarct expansion following myocardial ischemia.<b>NEW & NOTEWORTHY</b> BRD4 inhibition blocks stress-induced recruitment of pro-inflammatory monocytes to the heart. BRD4 inhibition reprograms resident cardiac macrophages toward a reparative phenotype marked by reduced NF-κB signaling and diminished MHC-II expression. BRD4 inhibition reduces infarct size in an acute model of ischemia/reperfusion injury in mice.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H294-H309"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880879","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}