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

{"title":"TREK-1- a Janus-faced and subcellular location-based regulator of cardiac remodeling in heart failure.","authors":"Patience Ofosuah, TingTing Hong","doi":"10.1152/ajpheart.00444.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00444.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493456","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":"Progress on Incorporating Sex as a Biological Variable in Cardiovascular Research.","authors":"Merry L Lindsey, Amanda J LeBlanc, Crystal M Ripplinger, Zamaneh Kassiri, Jonathan A Kirk, Petra Kleinbongard, Jason R Carter, Keith R Brunt","doi":"10.1152/ajpheart.00230.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00230.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493455","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":"New clues on sex-specific cerebrovascular aging.","authors":"Casey G Turner, Miranda E Good, Jennifer J DuPont","doi":"10.1152/ajpheart.00421.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00421.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493454","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":"Expression and function of β-site amyloid precursor protein cleaving enzyme 2 in vascular endothelium.","authors":"Livius V d'Uscio, Tetiana Kovalenko, Tongrong He, Trace A Christensen, Jeffrey L Salisbury, Zvonimir S Katusic","doi":"10.1152/ajpheart.00126.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00126.2025","url":null,"abstract":"<p><p>The physiological function of β-site amyloid precursor protein-cleaving enzyme 2 (BACE2) in vascular endothelium of systemic arteries is unknown. In the present study we generated conditional tamoxifen-inducible endothelial BACE2 deficient mice (eBACE2^-/- mice). Electron-microscopic and western blot analyses revealed that BACE2 protein is mainly present in endothelial cells of aorta. Genetic deletion of BACE2 in endothelial cells significantly impaired endothelium-dependent relaxations to Ca²⁺-ionophore A23187 in eBACE2^-/- aortas as compared to tamoxifen treated control mice irrespective of sex. Blockade of nitric oxide synthase (NOS) with <i>N</i>^ω-nitro-L-arginine methyl ester abolished relaxations to A23187. In contrast, endothelium-independent relaxations to nitric oxide donor diethylamine-NONOate were unchanged. Expression of endothelial NOS protein and levels of cyclic nucleotides were also unaffected in eBACE2^-/- mice. Further analysis of the mechanisms underlying impaired endothelial function demonstrated that treatment with thromboxane A₂ receptor antagonist SQ29548 ameliorated relaxations to A23187 in the aorta of male and female eBACE2^-/- mice. Furthermore, mRNA and protein expressions of cyclooxygenase-2 as well as production of thromboxane A₂ and prostaglandin F_2α were significantly increased in the aorta of eBACE2^-/- mice. In contrast, production of 6-keto prostaglandin F_1α and prostaglandin E₂ were not affected. In addition, ex-vivo treatment of wild-type aortas with proinflammatory cytokines decreased protein expression of BACE2. The results of our study suggest that increased production of vasoconstrictor prostanoids are responsible for impairment of endothelium-dependent relaxations to A23187 in the aorta of eBACE2^-/- mice. We report previously unrecognized role of BACE2 in control of endothelial arachidonic acid metabolism and vasomotor function.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473792","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 profiling of patients with a Fontan circulation using pulmonary pressure/flow relations during dobutamine stress and pulmonary vasodilation testing.","authors":"Floris-Jan S Ridderbos, Elke S Hoendermis, Gaston van Hassel, Tjark Ebels, Joost P van Melle, Rolf M F Berger","doi":"10.1152/ajpheart.00105.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00105.2025","url":null,"abstract":"<p><p>The hemodynamics of Fontan pathophysiology and the effects of pulmonary vasodilator therapy are insufficiently understood. The aim was to evaluate hemodynamic responses to dobutamine induced stress and the effect of concomitant acute pulmonary vasodilation testing (APV) in patients with a Fontan circulation to identify hemodynamic phenotypes. Sixteen adult patients undergoing cardiac catheterization for clinical indication were included. Hemodynamic phenotyping was performed during baseline, dobutamine induced stress and concomitant APV (inhaled nitric-oxide with F_IO₂ 1.0). Pulmonary vascular disease (PVD) was defined by pulmonary vascular resistance (PVR)>2Wood units or pulmonary artery pressure/pulmonary blood flow-slope (mPAP/Qp)>3mmHg/L/min. Patients were assigned to Group-A without PVD (N=8) or Group-B with PVD (N=8 mPAP/Qp>3 with N=3 PVR>2). For the total group; median cardiac output (Qs) was 5.2L/min and increased to 7.3L/min with dobutamine (p=0.005) without further change with APV (p=0.255). However, subgroup-analysis revealed that during dobutamine the increase in Qs occurred only in Group-A (+3.5L/min, p=0.012), and Qs decreased APV(-1.3L/min, p=0.0036). In contrast, in group-B Qs did not change with dobutamine (p=0.236), nor with APV (p=0.327). However, in contrast to group-A (p=0.889), in group-B Qp increased with APV(+1.3L/min, p=0.017) while the mPAP/Qp-slope improved significantly (6.2 to 1mmHg/L/min, p=0.017). Suggesting that APV improved Qp and oxygenation in patients with PVD, but had negative effects in those without PVD. This study shows that hemodynamic response to dobutamine induced stress and APV differs in patients with a Fontan circulation depending on the presence of pulmonary vascular disease. Hemodynamic phenotyping with sophisticated identification of pulmonary vascular disease potentially allows for patient-tailored treatment.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281992","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":"Restoration of extracellular matrix is key to extending life in a mouse model of medial arterial calcification.","authors":"Garrett W D Easson, Jessica E Wagenseil","doi":"10.1152/ajpheart.00394.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00394.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245926","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":"Mlc2v-Cre induces germline recombination in a sex-biased manner.","authors":"Termeh Aslani, Rimshah Abid, Reshani Jeyaratnam, Wenbin Liang, Kyoung-Han Kim","doi":"10.1152/ajpheart.00122.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00122.2025","url":null,"abstract":"<p><p>The myosin light chain-2 ventricular isoform (MLC2V), encoded by the <i>Myl2</i> gene, is a sarcomeric protein in ventricular cardiomyocytes, making Mlc2v-Cre mice (<i>Myl2</i>^{tm1(cre)Krc/AchakJ}) a valuable tool for ventricle-specific gene targeting. However, we observed unexpected recombination in nonmuscular tissues of offspring from Mlc2v-Cre breeders, suggesting off-target Cre activity and germline transmission. This study aims to quantify the prevalence and sex-dependency of off-target recombination in Mlc2v-Cre mice. To address this, Mlc2v-Cre mice were crossed with <i>Rosa26</i>^tdTomato reporter mice, and Cre-Lox recombination was visualized in the resulting embryos. Our results demonstrate that Mlc2v-Cre induces germline recombination in both male and female breeders, with a higher incidence in females, leading to the unintended generation of a whole body recombined allele, independent of <i>Cre</i> transgene, in the offspring. This was further supported by MLC2V and tdTomato expression in male and female germ cells. These findings highlight the importance of validating Cre-mediated recombination specificity to avoid confounding experiment outcomes and ensure accurate data interpretation.<b>NEW & NOTEWORTHY</b> Although the Mlc2v-Cre mouse line is widely used for ventricle-specific gene targeting in cardiac research, this study shows that both male and female Mlc2v-Cre mice can cause unexpected germline recombination, with a higher incidence in females. To avoid confounding results from whole body gene targeting, these findings underscore the need to validate off-target recombination.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1168-H1175"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966748","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":"TSP-1, TSP-2, and TSP-5 demonstrate sexual dimorphism in intimal hyperplasia in rats and mice.","authors":"Ashley A Peters, Furqan Muqri, Corinne Bunn, Mohammed Kassem, Alex Helkin, David Bruch, Kristopher G Maier, Vivian Gahtan","doi":"10.1152/ajpheart.00632.2024","DOIUrl":"10.1152/ajpheart.00632.2024","url":null,"abstract":"<p><p>Thrombospondins (TSPs) are matricellular proteins involved in intimal hyperplasia (IH). We hypothesized that <i>1</i>) TSP-1, TSP-2, and TSP-5 are interdependent regarding their effects on vascular smooth muscle (VSMC) physiology; <i>2</i>) local or systemic knockout of <i>THBS1</i> or <i>THBS2</i> reduces IH, with its combination (<i>THBS1/2</i>) being most effective; <i>3</i>) local or systemic knockout of <i>THBS5</i> increases IH; and <i>4</i>) the effects of TSPs differ between males and females. In vitro, VSMCs were transfected with siRNA against <i>THBS1</i>, <i>THBS2</i>, <i>THBS5</i>, or <i>THBS1/2.</i> VSMC proliferation by TSP-1, TSP-2, or PDGF-BB was tested, and chemotaxis to TSP-1, TSP-2, TSP-5, or PDGF-BB was assessed. Sprague-Dawley male and female rats underwent carotid artery balloon injury with intraluminal treatment of saline or adeno-associated virus containing siRNA against <i>THBS1</i>, <i>THBS2</i>, <i>THBS1/2</i>, <i>THBS5</i>, or scrambled siRNA. Wild-type, <i>THBS1</i>, <i>THBS2</i>, or <i>THBS5</i> null male or female mice underwent carotid artery ligation. After 14 days (rat) or 28 days (mice), animals were perfusion-fixed, euthanized, and IH measured. In vitro, siRNA to <i>THBS1</i>, <i>THBS2</i>, <i>THBS1/2</i>, or <i>THBS5</i> decreased VSMC response to exogenous TSPs. The novel combined siRNA <i>THBS1/2</i> demonstrated the most robust decrease in proliferation and migration. In vivo, only male rats and mice had reduced IH with local or systemic knock down of <i>THBS1</i> or <i>THBS2</i> (<i>P</i> < 0.05), with combined siRNA to <i>THBS</i>1/2 having the most robust effect. Knockdown of <i>THBS5</i> increased IH only in female mice (<i>P</i> < 0.05). In conclusion, TSPs affect one another and demonstrate a sexual dimorphism that may explain differences between male and female IH.<b>NEW & NOTEWORTHY</b> Thrombospondins (TSPs) are matricellular proteins involved in intimal hyperplasia (IH). We demonstrate in vitro, TSP-1, TSP-2, and TSP-5 affect one another and influence vascular smooth muscle cell proliferation and migration. In vivo, using a rat and mouse model of IH, we show that TSPs demonstrate a sexual dimorphism that may explain differences between male and female IH. Particularly, TSP-1 and TSP-2 appear to be strong mediators of IH in males only.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1296-H1305"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958921","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":"Cardiac energy substrate utilization in heart failure with preserved ejection fraction: reconciling conflicting evidence on fatty acid and glucose metabolism.","authors":"Lina A Shehadeh, Emely Robleto, Gary D Lopaschuk","doi":"10.1152/ajpheart.00121.2025","DOIUrl":"10.1152/ajpheart.00121.2025","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF) is characterized by complex metabolic derangements, yet considerable controversy exists regarding the role, and specifically the direction, of fatty acid oxidation (FAO) in disease progression. Through a systematic review with narrative synthesis of 44 studies identified from MEDLINE, Embase, and Web of Science databases, we critically examine the seemingly contradictory evidence regarding cardiac FAO in HFpEF. Our systematic analysis of experimental approaches reveals that many apparent contradictions can be resolved by considering differences in methodological approaches, interpretation of indirect metabolic markers, and the dynamic nature of metabolic adaptation in disease progression. Direct measurements consistently demonstrate that FAO remains active or increased in HFpEF hearts, whereas glucose oxidation becomes impaired, challenging previous assumptions based on indirect metabolic assessments. Methodological differences, particularly between studies using isolated mitochondria versus intact hearts and indirect versus direct substrate utilization measurements, can explain many apparent contradictions in the literature. Clinical and experimental evidence supports that FAO is maintained or elevated in HFpEF, with primary defects occurring in glucose oxidation and mitochondrial quality control. These findings suggest that successful therapeutic strategies for HFpEF should prioritize restoring metabolic flexibility and optimizing substrate utilization patterns rather than simply modulating FAO pathways. Our synthesis of the literature provides a comprehensive framework for understanding cardiac energy metabolism in HFpEF and identifies critical areas for future investigation.<b>NEW & NOTEWORTHY</b> Direct measurements reveal fatty acid oxidation remains active or increased in HFpEF hearts, whereas glucose oxidation becomes impaired, challenging previous assumptions. Apparent contradictions in HFpEF metabolism literature arise from methodological differences-studies using isolated mitochondria versus intact hearts. Evidence demonstrates fatty acid oxidation is maintained in HFpEF, with defects primarily in glucose oxidation. Successful therapeutic strategies should prioritize restoring metabolic flexibility rather than simply modulating fatty acid oxidation pathways.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1267-H1295"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957581","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":"Beclin-1-dependent autophagy protects perivascular adipose tissue function from hyperaldosteronism effects.","authors":"Rafael M Costa, Ariane Bruder-Nascimento, Juliano V Alves, Wanessa M C Awata, Shubhnita Singh, Daniel Rodrigues, Thiago Bruder-Nascimento, Rita C Tostes","doi":"10.1152/ajpheart.00829.2024","DOIUrl":"10.1152/ajpheart.00829.2024","url":null,"abstract":"<p><p>Hyperaldosteronism (HA), characterized by excessive production of aldosterone (Aldo), contributes to cardiovascular damage and perivascular adipose tissue (PVAT) dysfunction. Previous studies have shown that Aldo can impair autophagy in various tissues. However, it remains unclear whether this impairment occurs specifically in PVAT and whether it involves disruption of autophagic flux through Beclin-1 (BCN1), a key regulator of autophagosome formation and maturation. We hypothesize that BCN1-dependent autophagy plays a protective role in PVAT by limiting inflammation and preserving its anticontractile function in the context of HA. Male and female C57BL/6J [wild type (WT)] and BCN1 knock-in mice, aged 10-12 wk, underwent 14-day aldosterone infusion (600 µg/kg/day) using an osmotic minipump. Vascular function was assessed in PVAT-intact thoracic aortae, and blood pressure was monitored via radiotelemetry. HA disrupted PVAT autophagic flux, leading to the accumulation of LC3II/I and p62 proteins and reduced BCN1 expression/activity. In WT mice, PVAT exhibited an anticontractile effect, which was abolished by HA. In contrast, BCN1-knock-in mice were protected from this loss of PVAT function. HA also induced oxidative stress and inflammation in PVAT, as evidenced by increased reactive oxygen species generation and elevated mRNA levels of TNF-α, IL-6, IL-1β, and IL-17. These proinflammatory and prooxidative changes were not observed in BCN1-knock-in mice, indicating preserved PVAT homeostasis. Furthermore, pharmacological induction of autophagy via spermidine and activation of BCN1 with TB peptide improved PVAT function in HA-treated WT mice. Finally, BCN1-knock-in mice exhibited partial protection against HA-induced hypertension, highlighting the systemic vascular benefits of enhanced autophagic flux. In summary, our findings demonstrate that the activation of autophagy provides protection against HA-induced PVAT inflammation, dysfunction, and hypertension. Consequently, the activation of BCN1 could serve as a pharmacological strategy to prevent the harmful cardiovascular effects associated with HA.<b>NEW & NOTEWORTHY</b> Elevated aldosterone levels, as seen in primary hyperaldosteronism, obesity, and hypertension, impair autophagic flux in perivascular adipose tissue (PVAT), leading to increased inflammation and loss of anticontractile function. The Beclin-1-dependent autophagic pathway plays a key role in maintaining PVAT homeostasis and vascular tone. Disrupted autophagy contributes to oxidative stress and hypertension. Activating this pathway may offer a novel therapeutic strategy to mitigate aldosterone's harmful vascular effects in hypertension by restoring PVAT function and vascular inflammation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1253-H1266"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952576","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}