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}
{"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}
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}
{"title":"From signal to action: the roles of β<sub>1</sub>-adrenergic receptors in cardiac function and disease.","authors":"W Glen Pyle","doi":"10.1152/ajpheart.00151.2025","DOIUrl":"10.1152/ajpheart.00151.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H830-H831"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583797","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}
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}
Garrett Jensen, Xinjie Wang, Jacob Kuempel, Nicolas Palaskas, Zhishi Chen, Wei Yu, Yanping Chen, Haseeb Mohammad, Weijia Luo, Jiang Chang
{"title":"Immune checkpoint inhibitor-associated myocarditis: a historical and comprehensive review.","authors":"Garrett Jensen, Xinjie Wang, Jacob Kuempel, Nicolas Palaskas, Zhishi Chen, Wei Yu, Yanping Chen, Haseeb Mohammad, Weijia Luo, Jiang Chang","doi":"10.1152/ajpheart.00687.2024","DOIUrl":"10.1152/ajpheart.00687.2024","url":null,"abstract":"<p><p>The most fatal side effect associated with revolutionary immune checkpoint inhibitor (ICI) cancer therapies is myocarditis, a rare and devastating complication with a mortality rate approaching 40%. This review comprehensively examines the limited knowledge surrounding this recently recognized condition, emphasizing the absence of evidence-based therapeutic strategies, diagnostic modalities, and reliable biomarkers that hinder effective management. It explores advancements in preclinical models that are uncovering disease mechanisms and enabling the identification of therapeutic targets. These efforts have informed the design of early clinical trials aimed at reducing mortality. With the growing prevalence of ICI therapies in oncology, addressing critical gaps, such as long-term outcomes and risk stratification, has become increasingly urgent. By synthesizing current evidence, this work seeks to enhance understanding and guide the development of strategies to improve patient outcomes and ensure the continued safe use of ICIs in cancer care.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H734-H751"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381527","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}
Auni C Williams, Virginia G Content, Lacy M Alexander
{"title":"Salsalate negatively impacts microvascular function in women with endometriosis.","authors":"Auni C Williams, Virginia G Content, Lacy M Alexander","doi":"10.1152/ajpheart.00012.2025","DOIUrl":"10.1152/ajpheart.00012.2025","url":null,"abstract":"<p><p>Women with endometriosis, an inflammatory disease, are at increased risk of cardiovascular disease and demonstrate impaired microvascular endothelial function, characterized by reduced nitric oxide (NO)-mediated vasodilation. In some clinical cohorts, nuclear factor-kappa B (NFκB) inhibition with salsalate improves endothelial function. We hypothesized that salsalate would improve cutaneous microvascular endothelial function in women with endometriosis. Following placebo or salsalate (3,000 mg·day<sup>-1</sup> for 5 days), four intradermal microdialysis probes were placed in 11 women (33 ± 7 yr) with endometriosis. Local heating units (set to 33°C) and laser-Doppler flowmetry (red blood cell flux) probes were placed over the probes. Increasing doses of acetylcholine (ACh; dissolved in lactated Ringer's solution) were perfused, alone (control) or coperfused with: <i>N</i><sup>G</sup>-nitro-l-arginine methyl ester (l-NAME), atorvastatin (statin), or l-NAME + statin (combo). Maximal vasodilation was then induced (local heat at 43°C + sodium nitroprusside perfusion). Data were normalized as percentage of maximal cutaneous vascular conductance (CVC<sub>%max</sub> red blood cell flux/mean arterial pressure). To measure macrovascular endothelial function, flow-mediated dilation (FMD) was additionally performed. During placebo, coperfusion with statin did not impact the CVC<sub>%max</sub> ACh dose-response (<i>P</i> = 0.93). Oral salsalate attenuated the CVC<sub>%max</sub> response to ACh perfusion alone (<i>P</i> < 0.01) but did not impact the l-NAME site (<i>P</i> = 0.09). Salsalate significantly augmented the CVC<sub>%max</sub> response of the statin site (<i>P</i> < 0.01) but did not affect the combo site response (<i>P</i> = 1.00). FMD was not different between treatments (<i>P</i> = 0.79). Salsalate treatment impairs vasodilation in the cutaneous microcirculation in women with endometriosis through non-NO-dependent mechanisms.<b>NEW & NOTEWORTHY</b> Our results show that oral salsalate treatment negatively impacts microvascular function but does not alter macrovascular function. In contrast to the majority of other clinical populations with endothelial dysfunction, salsalate treatment reduces microcirculatory function through non-NO-dependent mechanisms in women with endometriosis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H915-H922"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565806","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}
Siluleko A Mkhize, Sulé Gunter, Ashmeetha Manilall, Lebogang Mokotedi, Kgotso L Mosoma, Refentshe Nthlane, Aletta M E Millen, Frederic S Michel
{"title":"Involvement of microRNA-146a-5p, but not -155-5p and -29b-5p, in left ventricular remodeling and dysfunction in spontaneously hypertensive rats.","authors":"Siluleko A Mkhize, Sulé Gunter, Ashmeetha Manilall, Lebogang Mokotedi, Kgotso L Mosoma, Refentshe Nthlane, Aletta M E Millen, Frederic S Michel","doi":"10.1152/ajpheart.00696.2024","DOIUrl":"10.1152/ajpheart.00696.2024","url":null,"abstract":"<p><p>The contribution of microRNAs remains poorly understood in the context of hypertensive cardiac pathology. The role of miR-146a-5p, miR-155-5p, and miR-29b-5p in cardiac hypertrophy and dysfunction was investigated in spontaneously hypertensive rats (SHRs). Seven-month-old SHR (<i>n</i> = 7 male, <i>n</i> = 9 female) and normotensive Wistar Kyoto rats (WKY; <i>n</i> = 7 male, <i>n</i> = 9 female) underwent echocardiography. Plasma concentrations of inflammatory markers were measured by ELISA. Interstitial and perivascular fibrosis and percentage macrophage infiltration were determined by histology. Left ventricular (LV) mRNA expressions of cardiac remodeling markers and miRNA expressions were determined by RT-PCR. Circulating vascular cell adhesion molecule-1 (VCAM-1), macrophage infiltration, interstitial and perivascular fibrosis, relative wall thickness (RWT), early diastolic mitral inflow to tissue lengthening velocity at lateral mitral annulus (E/e'), and LV mRNA expression of <i>NFKBIA</i> and <i>SOD2</i> were greater in SHRs. MidFS, e', and a' were lower in SHRs. Expression of <i>LOX1</i>, <i>Col1a/Col3a</i> ratio, circulating c-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and RWT were greater in females. No difference in miR-29b-5p expression was noted. MiR-155-5p expression was lower in female and associated with stroke volume and absolute heart and LV masses. MiR-146a-5p expression was greater in SHRs and associated with systolic blood pressure (SBP), circulating VCAM-1, macrophage infiltration, interstitial fibrosis, normalized heart and LV masses, RWT, and a'. MiR-146a-5p was also associated with circulating VCAM-1 after adjustments for SBP. In addition, greater expression of miRNA-146a-5p reversed the relationship between circulating VCAM-1 and macrophage infiltration. Changes in the expression of miR-155-5p may be involved with a cardiac phenotype related to sexual dimorphism. Conversely, upregulation of miR-146a-5p expression may act as a countermechanism induced by myocardial inflammation in the setting of reactive fibrosis, established LV hypertrophy, and impaired diastolic function.<b>NEW & NOTEWORTHY</b> We investigated roles of microRNAs-146a-5p, -155-5p, and -29b-5p in development of cardiac hypertrophy and dysfunction in SHRs. We showed that miR-146a-5p expression was upregulated in SHRs and positively associated with indices of concentric LVH and diastolic dysfunction, potentially as countermechanism in response to myocardial inflammation, whereas miR-155-5p was expressed in a manner consistent with sexual dimorphism. Our data may offer novel insights on involvement of miRNAs in myocardial inflammation in hypertension-induced cardiac hypertrophy and dysfunction.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H885-H899"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539933","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}
Eunhee Chung, David Zhang, Maria Gonzalez Porras, Chia George Hsu
{"title":"TREM2 as a Regulator of Obesity-Induced Cardiac Remodeling: Mechanisms and Therapeutic Insights.","authors":"Eunhee Chung, David Zhang, Maria Gonzalez Porras, Chia George Hsu","doi":"10.1152/ajpheart.00075.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00075.2025","url":null,"abstract":"<p><p>Obesity and type 2 diabetes mellitus (T2DM) are global health challenges that significantly increase the risk of cardiovascular diseases (CVD). Advances in immunometabolism have identified Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a key regulator of macrophage function, lipid metabolism, and inflammation resolution. While extensively studied in neurodegenerative diseases, TREM2's role in metabolic disorders and cardiovascular health is an emerging area of research. This review explores TREM2's molecular structure and functions, emphasizing its contributions to immunometabolic regulation in obesity and T2DM. Evidence from preclinical models demonstrates that TREM2 modulates macrophage-driven inflammatory responses, lipid clearance, plaque stability, fibrosis, and myocardial remodeling. Translational findings suggest that TREM2 expression correlates with cardiometabolic outcomes, underscoring its potential as a therapeutic target. Key knowledge gaps include TREM2's temporal dynamics during disease progression, sex-specific effects, and interactions with recruited or resident macrophage activation in obesity and T2DM. Integrating mechanistic and translational insights is critical to harness TREM2's immunoregulatory potential for improving CVD outcomes in metabolic disorders.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727483","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}
Gautham Yepuri, Syed Nurul Hasan, Vikas Kumar, Michaele B Manigrasso, Gregory Theophall, Alexander Shekhtman, Ann Marie Schmidt, Ravichandran Ramasamy
{"title":"Mechanistic underpinnings of AGEs-RAGE via DIAPH1 in ischemic, diabetic, and failing hearts.","authors":"Gautham Yepuri, Syed Nurul Hasan, Vikas Kumar, Michaele B Manigrasso, Gregory Theophall, Alexander Shekhtman, Ann Marie Schmidt, Ravichandran Ramasamy","doi":"10.1152/ajpheart.00685.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00685.2024","url":null,"abstract":"<p><p>Diabetes is a major risk factor for cardiovascular diseases. Patients with diabetes are at greater risk for morbidity and mortality post myocardial infarction. As the epidemic of diabetes continues at an alarming pace, identification of specific therapeutic interventions to protect diabetic patients from the devastating consequences of myocardial infarction is an urgent need. Advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids, accumulate in the diabetic circulation and heart. The interaction of AGEs with its key receptor, receptor for AGE or RAGE, contributes to cardiac injury and dysfunction. The discovery that intracellular domain of RAGE binds to the formin, DIAPH1, and that DIAPH1 is essential for RAGE ligand-mediated signal transduction, unveiled the specific cellular means by which RAGE functions and highlights a new target for therapeutic interruption of pathological RAGE signaling during myocardial infarction. This review delves into intrinsic mechanisms by which AGE-RAGE axis via RAGE-DIAPH1 driven DIAPH1-Mitofusin2 (MFN2) interaction modulates pathogenic inter-organelle communications and opens opportunities for intensive studies to uncover the comprehensive mechanisms that drive injury-provoking actions from the intracellular space. This review illustrates the potential therapeutic cardioprotective benefits of antagonism of RAGE-DIAPH1interactions in the diabetic heart.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707920","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}