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

{"title":"Breaking bad and taking sides: chamber-specific mitochondrial remodeling in Dsg2-linked arrhythmogenic cardiomyopathy.","authors":"Keaton E Minor, Chi Fung Lee, Hina Lateef Nizami","doi":"10.1152/ajpheart.00633.2026","DOIUrl":"10.1152/ajpheart.00633.2026","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H981-H983"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711113","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":"Role of ROS, soluble guanylate cyclase and cGMP in mouse lung development during hyperoxia.","authors":"My Linh Nguyen, Joann M Taylor, V Joseph Dudley, Gregory B Waypa, Paul T Schumacker","doi":"10.1152/ajpheart.00207.2026","DOIUrl":"10.1152/ajpheart.00207.2026","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is characterized by disruption of newborn lung alveolar and vascular development. Administration of supplemental O₂ predisposes to BPD by inducing oxidant stress in multiple subcellular compartments by augmenting reactive oxygen species (ROS) production. We studied the role of subcellular ROS in lung cyclic guanosine monophosphate (cGMP) signaling and its relationship to lung development in cells, embryonic lung explants, and newborn mice. Embryonic lung explants demonstrated increased mitochondrial ROS during hyperoxia. In hyperoxic human embryonic kidney 293T cells, ROS in the mitochondrial matrix, cytosol, and intermembrane space (IMS) increased. Those cells demonstrated impaired soluble guanylate cyclase (sGC)-cGMP responsiveness to a nitric oxide donor, a response prevented by the cytosolic glutathione mimetic ebselen as well as by the sGC activator, cinaciguat, but not by mitochondrial matrix-targeted ebselen or by expression of an H₂O₂ scavenger in the mitochondrial intermembrane space (IMS-Prdx5). Neonatal mice exposed to 75% O₂ for 2 wk exhibited alveolar simplification and pulmonary artery wall thickening that were not rescued by cinaciguat or the sGC stimulator, riociguat. However, previous work demonstrated that mitochondria-targeted antioxidants prevent hyperoxia-mediated inhibition of lung alveolar development. Collectively, these studies demonstrate that separate mechanisms underlie the effects of hyperoxia on cGMP signaling and alveolarization in the newborn lung, with cytosolic oxidant stress responsible for impairing cGMP signaling and mitochondrial matrix ROS mediating the hyperoxia-induced impairment in lung alveolar development. Hence, the impairments in cGMP signaling and lung alveolar development during hyperoxia involve oxidant stress in distinct subcellular compartments and occur through independent mechanisms.<b>NEW & NOTEWORTHY</b> Hyperoxia impairs NO-mediated cGMP generation by augmenting cytosolic ROS. Cinaciguat rescued cGMP responsiveness in hyperoxic cells, hence oxidative damage to sGC is responsible. Increases in ROS in hyperoxic embryonic mouse lungs recapitulated responses previously recorded in adult mice. Hence, unlike premature infants, late gestational lung antioxidant maturation in the mouse is robust. Defects in lung alveolarization induced by hyperoxia were not rescued by cinaciguat or riociguat; hence, impaired cGMP signaling does not impair lung alveolarization.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1000-H1011"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13555625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-TNF, pan-JAK, and JAK1-selective inhibition differentially alter mechanisms of flow-mediated dilation in human microvessels.","authors":"Annie Kleynerman Roels, Erin C Birch, Yoshinori Nishijima, Shelby N Hader, Andreas M Beyer, Preetika C Sinh","doi":"10.1152/ajpheart.00517.2026","DOIUrl":"10.1152/ajpheart.00517.2026","url":null,"abstract":"<p><p>Patients with chronic inflammatory disorders, including inflammatory bowel disease (IBD), carry an increased risk of cardiovascular disease. The 2022 ORAL Surveillance study reported that the pan-selective Janus kinase inhibitor (JAKi) tofacitinib was associated with increased risk of major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis compared with antitumor necrosis factor (anti-TNF) therapy. This prompted guideline changes regarding the use of all JAKis, including upadacitinib, a JAK1-selective drug approved for use in chronic inflammatory conditions, including IBD. However, the mechanism underlying JAKi-related MACE outcomes and the significance of JAK selectivity relative to TNF inhibition remain unclear. Microvascular dysfunction (MVD) is a predictor of MACE. Flow-mediated dilation (FMD) is a measure of MVD. Using an established ex vivo model of resistance arterioles isolated from adipose tissue, we performed the first mechanistic comparison of antitumor necrosis factor (anti-TNF; infliximab), pan-JAK inhibitor (tofacitinib), and JAK1-selective (upadacitinib) therapies on human microvascular endothelial function. Arterioles were obtained from low-cardiovascular-risk subjects of both sexes. Isolated microvessels were incubated with drugs of interest. Flow-mediated dilation (FMD), an assessment of MVD, was measured before and after nitric oxide (NO) synthase inhibition or hydrogen peroxide (H₂O₂) scavenging. No therapy statistically altered FMD magnitude, yet underlying mechanisms differed. Control and infliximab-treated vessels maintained physiologic NO-mediated dilation. Tofacitinib induced a shift toward pathologic H₂O₂-mediated dilation. Upadacitinib impaired NO-dependent dilation without evidence of compensatory H₂O₂ signaling. In summary, anti-TNF therapy and selective versus nonselective JAKi differentially modulate endothelial mechanisms of vasodilation, suggesting unique microvascular phenotypes with potential implications for cardiovascular risk.<b>NEW & NOTEWORTHY</b> This is the first ex vivo mechanistic comparison of antitumor necrosis factor therapy (infliximab) and selective (upadacitinib) versus nonselective (tofacitinib) Janus kinase inhibition in human microvessels. Flow-mediated dilation showed no statistical differences; however, the mechanisms driving endothelial dilation varied. We report a shift from nitric oxide- to hydrogen peroxide-mediated dilation with tofacitinib, a distinct phenotype with upadacitinib, and nitric oxide-dependent dilation with infliximab, suggesting differential effects of IBD therapies on microvascular endothelial physiology.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H894-H899"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700534","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":"Tailored anesthesia protocols for echo-based HFpEF phenotyping in C57BL6/N mice.","authors":"Julia Wingert, Leonard Haase, Eric Meinhardt, Norbert Frey, Philipp Schlegel","doi":"10.1152/ajpheart.00319.2026","DOIUrl":"10.1152/ajpheart.00319.2026","url":null,"abstract":"<p><p>Echocardiographic evaluation of diastolic function in murine heart failure with preserved ejection fraction (HFpEF) models remains challenging due to insufficient temporal resolution of current high-frequency Doppler probes at heart rates beyond 450 beats/min. Aiming to optimize anesthesia for diastolic assessment in mice, we compared standard isoflurane sedation with a combination of isoflurane and either of the negative chronotropic substances medetomidine or esmolol. Both combined anesthetic regimens preserved Doppler measurement accuracy while resulting in lower heart rates, better discernibility of separate Doppler velocity waves, and shorter examination times. However, the combination of isoflurane and medetomidine showed a superior safety profile, preservation of systolic function, and higher interrater reliability, recommending itself as a refined anesthetic protocol for echo-based HFpEF phenotyping in C57BL6/N mice.<b>NEW & NOTEWORTHY</b> Combining isoflurane with medetomidine for anesthesia in murine diastolic function echocardiography leads to lower heart rates with better discernibility of separate waves in Doppler velocity curves while preserving measurement accuracy and systolic function. This results in higher interrater reliability and shorter examination times, improving reproducibility and reducing stress for the animal.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H834-H841"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343777","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":"Sex as a biological variable in cardiovascular-kidney-metabolic syndrome: lessons from a diet-induced mouse model.","authors":"Horacio Osorio-Alonso, Laura G Sánchez-Lozada","doi":"10.1152/ajpheart.00630.2026","DOIUrl":"10.1152/ajpheart.00630.2026","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H900-H902"},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672917","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":"Lipidomics in aortic stenosis: beyond lipid lowering.","authors":"Giuliana G Repetti, Michael A Raddatz","doi":"10.1152/ajpheart.00513.2026","DOIUrl":"10.1152/ajpheart.00513.2026","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H487-H489"},"PeriodicalIF":3.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315173","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":"Beyond cancer: breast cancer gene 2 emerges as a new player in atherosclerosis.","authors":"David C R Michels, Aman Singh, Margi Patel, Berk Rasheed, Sepideh Nikfarjam, Shuhan Bu, Mehroz Ehsan, Biao Feng, Liliana German-Castelan, Robert Gros, Jefferson C Frisbee, Krishna K Singh","doi":"10.1152/ajpheart.00790.2025","DOIUrl":"10.1152/ajpheart.00790.2025","url":null,"abstract":"<p><p>Atherosclerosis is a chronic immunoinflammatory disease driven by endothelial dysfunction, oxidative stress, and DNA damage. Although breast cancer gene 2 (<i>BRCA2</i>) is a key regulator of homologous recombination-mediated DNA damage repair, its role in vascular biology remains unclear. We hypothesized that endothelial BRCA2 protects against atherogenesis under stress conditions. Endothelial-specific BRCA2 knockdown mice (<i>BRCA2</i>^EC-KO) were generated using a vascular endothelial (VE)-cadherin-Cre/loxP system. Baseline phenotyping included assessment of DNA damage, apoptosis, cardiac function, and metabolic parameters. Subsequently, <i>BRCA2</i>^EC-KO mice were generated on an <i>ApoE^-/-</i> background (<i>BRCA2</i>^EC-KO;<i>ApoE^-/-</i>) and characterized. Atherosclerosis was then evaluated in the aorta following high-fat diet (HFD), with quantification of plaque burden, necrotic core area, collagen content, and macrophage infiltration. Plasma lipid levels were measured. Mechanistic studies included RNA sequencing of aortic tissue and in vitro experiments in <i>BRCA2</i>-silenced cultured endothelial cells treated with oxidized LDL (oxLDL), assessing unfolded protein response (UPR) and heme oxygenase-1 (HO-1) expression. Loss of endothelial BRCA2 had no effect on baseline viability, DNA damage, apoptosis, cardiac function, or metabolism in <i>BRCA2</i>^EC-KO mice. However, <i>BRCA2</i>^EC-KO;<i>ApoE^-/-</i> mice exhibited significantly increased plaque burden, necrotic core formation, collagen deposition, and vascular inflammation after HFD, without changes in plasma lipids. These mice also developed splenomegaly with reduced HO-1 expression. Transcriptomic analysis revealed enrichment of pathways related to UPR, oxidative stress, and cholesterol metabolism. In vitro, BRCA2 deficiency exacerbated oxLDL-induced UPR and attenuated HO-1 expression. These findings identify endothelial BRCA2 as a critical regulator of vascular stress responses and atheroprotection, revealing a previously unrecognized link between DNA repair pathways and cardiovascular disease.<b>NEW & NOTEWORTHY</b> This study uncovers a novel role for endothelial BRCA2 in limiting atherosclerosis. Endothelial cell-specific loss of BRCA2 is dispensable at baseline, but under high-fat diet stress, it significantly worsens atherosclerosis and causes splenomegaly. BRCA2 also regulates pathways beyond DNA repair in endothelial cells. These findings identify a new potential therapeutic target for atherosclerosis and suggest that individuals with BRCA2 mutations may have increased cardiovascular risk, expanding the known impact of BRCA2 beyond cancer susceptibility.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H717-H735"},"PeriodicalIF":3.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417984","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":"Neutralization of reactive oxygen species with cobinamide augments aortic dissections and rupture in BAPN-administered mice.","authors":"Alexis Richard, Zhen Zhou, Jose Emiliano Esparza Pinelo, Callie S Kwartler, Hema Kalyanaraman, Gerry R Boss, Hong S Lu, Alan Daugherty, Dianna M Milewicz","doi":"10.1152/ajpheart.00314.2026","DOIUrl":"10.1152/ajpheart.00314.2026","url":null,"abstract":"<p><p>Thoracic aortic aneurysms involving the root and ascending aorta progressively enlarge and can lead to life-threatening acute aortic dissections, collectively termed thoracic aortic disease (TAD). Oxidative stress due to an excess of reactive oxygen species (ROS) has been implicated in TAD pathogenesis by promoting vascular inflammation, extracellular matrix degradation, and smooth muscle cell apoptosis. Cobinamide (Cbi), a potent antioxidant and vitamin B12 analog, has been reported to slow aortic aneurysm growth in TAD mouse models. We evaluated its efficacy in mice administered β-aminopropionitrile (BAPN) to induce TAD, a model in which aneurysms progress to dissections. C57BL/6J mice of both sexes were administered either BAPN alone or BAPN plus Cbi in drinking water from <i>postnatal day 21</i> (P21). Survival analysis showed that 56% of mice in the BAPN group died from aortic rupture by P49, whereas mortality increased to 91% in the BAPN + Cbi group (<i>P</i> = 0.049). Necropsy confirmed thoracic aortic rupture as the cause of death. At P35, proximal aortic analyses showed that Cbi significantly reduced ROS abundance in the ascending aorta, based on decreased dihydroethidium staining and lower oxidative stress markers, including protein carbonylation and DNA oxidation by 8-hydroxy-deoxyguanosine staining. Cbi did not affect aortic diameters by echocardiography or elastic fiber fragmentation. Cbi was associated with reduced oxidative stress in aortic tissue; it did not prevent aortic dissection and was associated with increased rupture-related mortality in the BAPN model. These findings highlight context-dependent roles of ROS in TAD and the importance of carefully evaluating antioxidant strategies in dissection-prone settings.<b>NEW & NOTEWORTHY</b> Cobinamide reduced oxidative stress in aortas of mice administered BAPN but was associated with worsened fatal aortic dissections, highlighting a context-dependent role of redox signaling in aortic disease and the need for careful evaluation of antioxidant therapies intended to prevent thoracic aortic dissection.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H498-H505"},"PeriodicalIF":3.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the link between eosinophils and HIV-associated cardiac fibrosis: a new perspective on cardiovascular risk.","authors":"Eman Teer, Nyasha C Mukonowenzou, Megan Cairns, M Faadiel Essop","doi":"10.1152/ajpheart.00359.2026","DOIUrl":"10.1152/ajpheart.00359.2026","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H710-H713"},"PeriodicalIF":3.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443798","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":"Clinical utility of single ventricular stroke work index for predicting prognosis in patients with functional single ventricle.","authors":"Rumi Haneda, Takashi Honda, Ryuta Nakamura, Manabu Takanashi, Fumiaki Shikata, Yoichiro Hirata, Kagami Miyaji, Kenji Ishikura","doi":"10.1152/ajpheart.00948.2025","DOIUrl":"10.1152/ajpheart.00948.2025","url":null,"abstract":"<p><p>Stroke work of the ventricle is a parameter that integrates ventricular systolic and diastolic function. However, its clinical application in single-ventricle physiology has not been established. Thus, we defined a single ventricular stroke work index (SVSWI) and evaluated its ability to predict the prognosis of patients with single-ventricle physiology. On the basis of the results of cardiac catheterization before the Glenn procedure, we calculated the SVSWI using the following equation: SVSWI = (systemic blood flow + pulmonary blood flow)/heart rate/body surface area × (mean aortic pressure - pulmonary arterial wedge pressure) × 0.0136. We evaluated the ability of the SVSWI to predict the rate of patients completing the Fontan procedure within 2 yr after the catheterization, event-free survival, and mortality. We also investigated the relationships between SVSWI and patients' hemodynamic parameters 1 yr after Fontan completion. Forty-three patients were enrolled and divided into a high-SVSWI group (<i>group H</i>, SVSWI > 54.0 g·m/m², <i>n</i> = 23) and a low-SVSWI group (<i>group L</i>, SVSWI < 54.0 g·m/m², <i>n</i> = 20). The rate of Fontan completion was significantly greater in <i>group H</i> than in <i>group L</i> (100% vs. 80%, <i>P</i> = 0.0243). Survival and event-free survival were also significantly greater in <i>group H</i> (<i>P</i> = 0.0248 and 0.0050, respectively). The pre-Glenn SVSWI was positively correlated with cardiac output, mean blood pressure, venous oxygen saturation, and SVSWI after the Fontan procedure. In conclusion, the SVSWI is a valuable prognostic predictor for patients with single-ventricle physiology regardless of the underlying heart disease or ventricular morphology.<b>NEW & NOTEWORTHY</b> We defined a single ventricular stroke work index (SVSWI) specifically to evaluate single-ventricle physiology, and investigated its usefulness as a prognostic predictor in patients with single-ventricle physiology. We demonstrated that the pre-Glenn SVSWI can predict the completion of Fontan surgery, survival, and avoidance of cardiac events. These findings are supported by our data showing that the pre-Glenn SVSWI is correlated with parameters associated with single ventricular function after Fontan completion.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H579-H587"},"PeriodicalIF":3.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395607","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}