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

{"title":"Cardiac health, type I collagen, and aging in the <i>oim/oim</i> mouse model of osteogenesis imperfecta and a cohort of adults with OI.","authors":"Brittany N Lafaver, Li Lee, Chloe E Derocher, Lawrence F Levin, Erin M Carter, Krish Sardesai, Julian A Vallejo, Ali McAllister-Day, Tara K Crawford, Isabel M Chapman, Michael J Wacker, Cathleen L Raggio, Lixin Ma, Maike Krenz, Charlotte L Phillips","doi":"10.1152/ajpheart.00535.2024","DOIUrl":"10.1152/ajpheart.00535.2024","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with marked skeletal fragility and increased recognition as a pleiotropic type I collagenopathy. The impact of OI-causing gene variants on cardiac health and lifespan is just beginning to be understood. To begin to investigate cardiac manifestations of OI-causing type I collagen variants, we utilized the osteogenesis imperfecta murine (<i>oim/oim</i>) model to examine survival with increased age, as well as cardiac function and collagen expression at 4 and 18 mo of age. We determined male <i>oim/oim</i> mice had 50% decreased survival by 18 mo of age compared with wild-type (WT) littermates. Cardiac magnetic resonance imaging and echocardiography revealed 18-mo-old male <i>oim/oim</i> mice had increased left ventricular end-diastolic and end-systolic volumes concomitant with decreased function, as well as the presence of aortic stenosis in a subset of 4- and 18-mo-old male <i>oim/oim</i> mice compared with WT littermates. Female <i>oim/oim</i> survival and cardiac function were equivalent to their WT counterparts. Cardiac evaluations of an adult patient cohort with OI corroborated increased incidences of valvular dysfunction in the patient population with OI, with much of the male cohort also presenting with altered left ventricular function. Little is known concerning the impact of OI-causing variants on patient cardiac health and the influence of sex and age. Using an OI mouse model, we determined that 18-mo-old male <i>oim/oim</i> mice have cardiac dysfunction with decreased lifespan, confirming the need for further investigations to understand pleiotropic extraskeletal manifestations and disease progression in osteogenesis imperfecta.<b>NEW & NOTEWORTHY</b> The heritable skeletal dysplasia, osteogenesis imperfecta (OI), recently recognized as a pleiotropic collagenopathy, shows growing evidence of cardiac involvement impacting lifespan. Evaluating cardiac function (magnetic resonance imaging and echocardiography) using an OI mouse model revealed increased left ventricular end-diastolic and end-systolic volumes concomitant with decreased function and reduced survival in 18-mo-old male OI mice. Additional cardiac evaluations of an adult patient cohort with OI corroborated increased incidences of valvular dysfunction in the patient population with OI.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H565-H580"},"PeriodicalIF":4.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188202","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":"Extracellular matrix instability and chronic inflammation underlie maladaptive right ventricular pressure overload remodeling and failure in male mice.","authors":"Ilaria Russo, Wen Dun, Swasti Mehta, Sowda Ahmed, Christos Tzimas, Nobuaki Fukuma, Emily J Tsai","doi":"10.1152/ajpheart.00331.2024","DOIUrl":"10.1152/ajpheart.00331.2024","url":null,"abstract":"<p><p>Right ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or disease etiology. In both, RVD arises from chronic RV pressure overload and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of patients, however, differ by sex. Men develop more severe RVD and die at younger ages than women do. Mechanistic details of this sexual dimorphism in RV pressure overload remodeling are incompletely understood. We sought to elucidate the cardiac histologic and molecular pathophysiology underlying the sex-specific RV remodeling phenotypes, maladaptive [decompensated RVD with RV failure (RVF)] versus adaptive (compensated RVD). We subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9 wk. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, and histologic and molecular analyses. M-PAB developed severe RVD with RV failure (RVF), increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and recruitment and activation of macrophages. Despite equal severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF. ECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in M-PAB. These two RV remodeling phenotypes suggest that adverse ECM remodeling and chronic inflammation are also sex-dependent, thereby contributing to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention.<b>NEW & NOTEWORTHY</b> We compared pressure overload-induced RV remodeling in adult male versus female mice subjected to PAB. This study discovered an association between severe RVD, RVF, ECM instability, and chronic inflammation in pressure-overloaded RV of male PAB mice. These features distinguished maladaptive RV remodeling in male from adaptive RV remodeling in female PAB mice. In male patients with RV pressure overload due to HF or PAH, enhancing ECM stability and countering the recruitment of macrophages may help preserve RV function such that RVF could be prevented or delayed.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H676-H692"},"PeriodicalIF":4.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827057","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":"Insights into the effect of pre- and postnatal nicotine exposure on cardiovascular development and function.","authors":"Benjamin Rodriguez, Ashton Oliver, Han Le, Chanel Harris, Andrea G Marshall, Pamela Martin, Amadou Gaye, Lori Banks, Antentor Hinton","doi":"10.1152/ajpheart.00768.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00768.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456529","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":"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":"https://doi.org/10.1152/ajpheart.00893.2024","url":null,"abstract":"<p><p><b>Background:</b> 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 pro-inflammatory 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). <b>Methods:</b> Endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery by duplex ultrasound at the baseline exam. Baseline peripheral blood T-cell subsets were measured using flow cytometry (N=968). Two analyses were employed. 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. <b>Results:</b> 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. <b>Conclusions:</b> These results may suggest regulation of endothelial function by T-cells in pre-clinical 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.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mechanisms of Chr.9p21.3 risk locus in coronary artery disease: where are we today?","authors":"Anna-Kaisa Ruotsalainen, Sanna Kettunen, Tuisku Suoranta, Minna U Kaikkonen, Seppo Ylä-Herttuala, Rédouane Aherrahrou","doi":"10.1152/ajpheart.00580.2024","DOIUrl":"10.1152/ajpheart.00580.2024","url":null,"abstract":"<p><p>Despite the advancements and release of new therapeutics in the past few years, cardiovascular diseases (CVDs) have remained the number one cause of death worldwide. Genetic variation of a 9p21.3 genomic locus has been identified as the most significant and robust genetic CVD risk marker on the population level, with the strongest association with coronary artery disease (CAD) and other diseases, including diabetes and cancer. Several mechanisms of 9p21.3 in CVDs have been proposed, but their effects on CVDs have remained elusive. Moreover, most of the single nucleotide polymorphisms (SNPs) associated with CAD are located on a sequence of a long noncoding RNA (lncRNA) called <i>ANRIL</i>. <i>ANRIL</i> has several linear and circular splicing isoforms, which seem to have different effects and implications for CVDs. The mechanisms of the 9p21.3 locus and the interplay of its coding and noncoding transcripts in different diseases require further research. Circular RNAs have generally raised interest due to their beneficial features as biomarkers and therapeutic molecules. Here, we review the literature of 9p21.3 from its identification in 2007 and draw the current knowledge on its function, implications in CVDs, and therapeutic potential.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H196-H208"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799013","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":"Prenatal dexamethasone programs autonomic dysregulation in female rats.","authors":"Lakshmi Madhavpeddi, Monique Martinez, Jared Alvarez, Arpan Sharma, Chengcheng Hu, Stuart A Tobet, Taben M Hale","doi":"10.1152/ajpheart.00075.2024","DOIUrl":"10.1152/ajpheart.00075.2024","url":null,"abstract":"<p><p>Autonomic dysfunction is associated with cardiovascular and neurological diseases, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEX in utero [<i>gestation days</i> (GD) <i>18</i>-<i>21</i>]. At 11-12-wk of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (α₁-adrenoceptor + β₁-adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in the adrenals and left ventricle, and expression of the β₁ adrenergic receptor, choline acetyltransferase, and acetylcholinesterase were measured in the left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry.<b>NEW & NOTEWORTHY</b> Pharmacological antagonists are used to characterize the nature of the autonomic dysregulation induced in female offspring exposed to dexamethasone, in utero. The female offspring of dams injected with dexamethasone in late gestation show a reduction in vulnerability to parasympathetic blockade and an increase in responses to acute restraint stress even in the presence of sympathetic blockade. This suggests that late gestation dexamethasone disrupts the normal development of the autonomic function in females, shifting sympathovagal balance.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H209-H220"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880884","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":"Programming the heart: prenatal glucocorticoids and sex-specific cardiovascular risk.","authors":"Jessica L Caldwell","doi":"10.1152/ajpheart.00884.2024","DOIUrl":"10.1152/ajpheart.00884.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H245-H246"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909032","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":"Hyperglycemia inhibits AAA expansion: examining the role of lysyl oxidase.","authors":"Kathryn E Jespersen, Wanfen Xiong, Lakshmi Santhanam, Michael Terrin, Jon Matsumura, John A Curci, William Blackwelder, Clayton H Brown, Marta Martinez Yus, B Timothy Baxter","doi":"10.1152/ajpheart.00163.2024","DOIUrl":"10.1152/ajpheart.00163.2024","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is a common, progressive, and potentially fatal dilation of the most distal aortic segment. Multiple studies with longitudinal follow-up of AAA have identified markedly slower progression among patients affected with diabetes. Understanding the molecular pathway responsible for the growth inhibition could have implications for therapy in nondiabetic patients with AAA. Toward this end, we investigated the effects of hyperglycemia in a murine model of AAA and a carefully monitored cohort of patients with AAA from the Noninvasive Treatment of AAA-Clinical Trial (NTA3CT). In mice with hyperglycemia, AAA growth was inhibited to a similar degree (∼30%) as seen in patients with diabetes. AAA growth correlated inversely to levels of hyperglycemia in mice and patients with AAA. Inhibiting lysyl oxidase (LOX) activity increases aneurysm growth and matrix degradation in this model. Hyperglycemia increased LOX concentration in aortic smooth muscle cells (SMCs) but not in murine AAA tissue. Inhibiting LOX activity completely blocked the growth-inhibitory effect of hyperglycemia. Lysyl oxidase-like 2 (LOXL2), the primary arterial isoform of LOX, is expressed in the same area as type IV collagen along the outer media in murine AAA tissue. There is a significant inverse correlation between LOXL2 and AAA growth rates in patients. Taken together, these studies suggest a role for LOXL2-mediated type IV collagen crosslinking in slowing AAA growth in the setting of hyperglycemia.<b>NEW & NOTEWORTHY</b> AAA grows slower in patients affected by diabetes. This growth inhibition is lost when the enzyme lysyl oxidase (LOX) is blocked in diabetic mice. The predominant arterial isoform of LOX, LOX-like 2 (LOXL2), overlaps with type IV collagen in the outer media of murine aneurysm tissue. Circulating LOXL2 correlates inversely with AAA growth in patients. Type IV collagen cross-linking by LOXL2 may play a role in the AAA growth inhibition associated with diabetes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H247-H259"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880882","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":"Short-term estradiol administration does not restore endothelin-B receptor-mediated vasodilation in postmenopausal women.","authors":"Virginia R Nuckols, Leena N Shoemaker, Andrew V Kuczmarski, Katherine M Haigh, Shane J McGinty, Angelica R Del Vecchio, Allyson I Schwab, David G Edwards, Hugh S Taylor, Megan M Wenner","doi":"10.1152/ajpheart.00815.2024","DOIUrl":"10.1152/ajpheart.00815.2024","url":null,"abstract":"<p><p>The endothelin-B receptor (ET_BR) mediates vasodilation in young women, an effect that is absent in postmenopausal women. We have previously demonstrated that ET_BR-mediated vasodilation is regulated by estradiol (E₂) in young women; however, the impact of E₂ on ET_BR function in postmenopausal women remains unknown. Accordingly, the objective of this study was to test the hypothesis that E₂ exposure restores ET_BR-mediated dilation in postmenopausal women. Ten healthy postmenopausal women (55 ± 2 yr of age, 5 ± 3 years since menopause) completed the study. E₂ was administered by transdermal patch for 7 days (0.1 mg/day, Vivelle-Dot patch). Vasodilation in the cutaneous microcirculation (microvascular endothelial function) was measured via local heating (42°C) using laser Doppler flowmetry combined with intradermal microdialysis perfusions of lactated Ringer's (control) and ET_BR antagonist (BQ-788, 300 nM) at baseline and after E₂ administration. There was no effect of E₂ on ET_BR function [hormone × site, <i>F</i>(1,9) = 0.77, <i>P</i> = 0.40]. These data demonstrate that in contrast to findings in premenopausal women, E₂ administration does not restore ET_BR function in postmenopausal women.<b>NEW & NOTEWORTHY</b> The vascular endothelial endothelin-B receptor (ET_BR) mediates vasodilation in premenopausal women, an effect modulated by estradiol. ET_BR-mediated vasodilation is lost in postmenopausal women, but the effect of exogenous estradiol administration on ET_BR function in postmenopausal women is not known. During estradiol administration, ET_BR blockade did not affect cutaneous microvascular vasodilatory response to local heating. We demonstrate that exogenous estradiol administration does not restore ET_BR-mediated vasodilation in postmenopausal women.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H327-H332"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942591","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":"Effect of cardiomyocyte-specific lipid phosphate phosphatase 3 overexpression on high-fat diet-induced cardiometabolic dysfunction in mice.","authors":"Anu Jose, Shanmugasundaram Pakkiriswami, Angella Mercer, Yadab Paudel, Esther Yi, Jeffy Fernando, Thomas Pulinilkunnil, Petra C Kienesberger","doi":"10.1152/ajpheart.00518.2024","DOIUrl":"10.1152/ajpheart.00518.2024","url":null,"abstract":"<p><p>Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3^OE mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3^FL) and LPP3^OE mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 wk, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3^OE mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared with LPP3^FL mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3^OE mice were protected from increased plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared with LPP3^FL mice. Female LPP3^OE mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy.<b>NEW & NOTEWORTHY</b> Lipid phosphate phosphatase 3 (LPP3) hydrolyzes bioactive lipids including lysophosphatidic acid (LPA), elevated levels of which are implicated in obesity-induced metabolic and cardiac dysfunction. We show that cardiac-specific overexpression of LPP3 lowers plasma LPA levels, blunts LPA signaling in cardiomyocytes, and increases pyruvate-linked mitochondrial respiration in the heart at baseline in both male and female mice. In female mice, LPP3 overexpression also protects from high-fat diet-induced obesity, insulin resistance, and cardiac dysfunction.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H333-H347"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976990","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}