Circulation research最新文献

{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000710","DOIUrl":"https://doi.org/10.1161/RES.0000000000000710","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 5","pages":"453-454"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Better Late Than Early? The Role of the Vascular Endothelium in Late-Onset Menopause.","authors":"Gurleen Kaur, Naomi M Hamburg, Emily S Lau","doi":"10.1161/CIRCRESAHA.125.326197","DOIUrl":"10.1161/CIRCRESAHA.125.326197","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 5","pages":"470-472"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preservation of Vascular Endothelial Function in Late-Onset Postmenopausal Women.","authors":"Sanna Darvish, Kevin O Murray, Katelyn R Ludwig, Krisha H Avalani, Daniel H Craighead, Kaitlin A Freeberg, Shaun Bevers, Julie A Reisz, Angelo D'Alessandro, Kerrie L Moreau, Douglas R Seals, Matthew J Rossman","doi":"10.1161/CIRCRESAHA.124.325639","DOIUrl":"10.1161/CIRCRESAHA.124.325639","url":null,"abstract":"<p><strong>Background: </strong>Postmenopausal women (PMW) who complete menopause at a late age (55+ years) have lower cardiovascular disease risk than PMW who complete menopause at a normal age (45-54 years). However, the influence of late-onset menopause on vascular endothelial dysfunction is unknown. Moreover, the mechanisms by which a later age at menopause may modulate endothelial function remain to be determined.</p><p><strong>Methods: </strong>We measured endothelial function (brachial artery flow-mediated dilation [FMD_BA]) in age-matched late- and normal-onset PMW and a young premenopausal reference group. We determined mitochondrial reactive oxygen species (mitoROS)-related suppression of endothelial function (change in FMD_BA with an acute dose of the mitochondria-targeted antioxidant MitoQ; ΔFMD_{BA, MTQ}) in PMW. The effects of serum from late- and normal-onset PMW and premenopausal women on mitoROS bioactivity in human aortic endothelial cells in culture were assessed. Metabolomics analyses in combination with serum metabolite level normalization and human aortic endothelial cell serum exposure experiments were performed to identify the circulating factors contributing to the serum effects on endothelial cell mitoROS bioactivity.</p><p><strong>Results: </strong>FMD_BA in PMW was lower than in premenopausal women. However, FMD_BA was >50% higher in late- versus normal-onset PMW and positively related to age at menopause. ΔFMD_{BA, MTQ} was >50% lower in late- versus normal-onset PMW. Serum from normal-onset PMW but not late-onset PMW induced higher mitoROS bioactivity in human aortic endothelial cells compared with serum from premenopausal women. MitoROS bioactivity was negatively related to FMD_BA and age at menopause. Seventeen metabolites significantly differed between late- and normal-onset PMW; 15 were lipid specific; 8 were triglyceride derived. TG(16:0) was most strongly correlated with mitoROS bioactivity. Normalization of TG(16:0) concentrations in serum from premenopausal women and late-onset PMW to match serum levels in normal-onset PMW abrogated differences in mitoROS bioactivity in serum-treated human aortic endothelial cells.</p><p><strong>Conclusions: </strong>Late-onset menopause is associated with preservation of endothelial function, which is mediated by lower mitoROS-associated oxidative stress. A more favorable profile of circulating lipid metabolites, specifically triglyceride-derived metabolites, contributes to lower endothelial cell mitoROS in late-onset PMW. These findings provide new insight into the possible mechanisms of reduced cardiovascular disease risk in late-onset menopause.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"455-469"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Therapeutic Approach Targeting CXCR3 to Treat Immunotherapy Myocarditis.","authors":"Yuhsin Vivian Huang, Yin Sun, Harrison Chou, Noah Wagner, Maria Rosaria Vitale, Abraham L Bayer, Bruce Xu, Daniel Lee, Zachary Lin, Corynn Branche, Sarah Waliany, Joel W Neal, Heather A Wakelee, Ronald M Witteles, Patricia K Nguyen, Edward E Graves, Gerald J Berry, Pilar Alcaide, Sean M Wu, Han Zhu","doi":"10.1161/CIRCRESAHA.124.325652","DOIUrl":"10.1161/CIRCRESAHA.124.325652","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) are successful in treating many cancers but may cause immune-related adverse events. ICI-mediated myocarditis has a high fatality rate with severe cardiovascular consequences. Targeted therapies for ICI myocarditis are currently limited.</p><p><strong>Methods: </strong>We used a genetic mouse model of PD1 deletion (<i>MRL/Pdcd1</i>^<i>-/-</i>) along with a novel drug-treated ICI myocarditis mouse model to recapitulate the disease phenotype. We performed single-cell RNA-sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes on immune cells isolated from <i>MRL</i> and <i>MRL/Pdcd1</i>^<i>-/-</i> mice at serial time points. We assessed the impact of macrophage deletion in <i>MRL/Pdcd1</i>^<i>-/-</i> mice, then inhibited CXCR3 (C-X-C motif chemokine receptor 3) in ICI-treated mice to assess the therapeutic effect on myocarditis phenotype. Furthermore, we delineated the functional and mechanistic effects of CXCR3 blockade on T-cell and macrophage interactions. We then correlated the results in human single-cell multiomics data from blood and heart biopsy data from patients with ICI myocarditis.</p><p><strong>Results: </strong>Single-cell multiomics demonstrated expansion of CXCL (C-X-C motif chemokine ligand) 9/10+CCR2+ macrophages and CXCR3hi (C-X-C motif chemokine receptor 3 high-expressing) CD8+ (cluster of differentiation) effector T lymphocytes in the hearts of <i>MRL/Pdcd1</i>^<i>-/-</i> mice correlating with onset of myocarditis development. Both depletion of CXCL9/10+CCR2+ (C-C motif chemokine receptor) macrophages and CXCR3 blockade, respectively, led to decreased CXCR3hi CD8+ T-cell infiltration into the heart and significantly improved survival. Transwell migration assays demonstrated that the selective blockade of CXCR3 and its ligand, CXCL10, reduced CXCR3+CD8+ T-cell migration toward macrophages, implicating this interaction in T-cell cardiotropism toward cardiac macrophages. Furthermore, cardiomyocyte apoptosis was induced by CXCR3hi CD8+ T cells. Cardiac biopsies from patients with confirmed ICI myocarditis demonstrated infiltrating CXCR3+ T cells and CXCL9+/CXCL10+ macrophages. Both mouse cardiac immune cells and patient peripheral blood immune cells revealed expanded TCRs (T-cell receptors) correlating with CXCR3hi CD8+ T cells in ICI myocarditis samples.</p><p><strong>Conclusions: </strong>These findings bring forth the CXCR3-CXCL9/10 axis as an attractive therapeutic target for ICI myocarditis treatment, and more broadly as a druggable pathway in cardiac inflammation.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"473-490"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Microbiota Metabolites Sensed by Host GPR41/43 Protect Against Hypertension.","authors":"Rikeish R Muralitharan, Tenghao Zheng, Evany Dinakis, Liang Xie, Anastasia Barbaro-Wahl, Hamdi A Jama, Michael Nakai, Madeleine Paterson, Kwan Charmaine Leung, Zoe McArdle, Katrina Mirabito Colafella, Chad Johnson, Wendy Qin, Ekaterina Salimova, Natalie J Bitto, Maria Kaparakis-Liaskos, David M Kaye, Joanne A O'Donnell, Charles R Mackay, Francine Z Marques","doi":"10.1161/CIRCRESAHA.124.325770","DOIUrl":"10.1161/CIRCRESAHA.124.325770","url":null,"abstract":"<p><strong>Background: </strong>Fermentation of dietary fiber by the gut microbiota leads to the production of metabolites called short-chain fatty acids, which lower blood pressure and exert cardioprotective effects. Short-chain fatty acids activate host signaling responses via the functionally redundant receptors GPR41 (G-protein-coupled receptor 41) and GPR43 (G-protein-coupled receptor 43), which are highly expressed by immune cells. Whether and how these receptors protect against hypertension or mediate the cardioprotective effects of dietary fiber remains unknown.</p><p><strong>Methods: </strong>Cardiovascular phenotype was assessed in untreated and Ang II (angiotensin II) treated hypertensive wild-type and GPR41/43 knockout (KO) double knockout male mice fed diets with different levels of fiber content. Some mice received TLR4 (toll-like receptor 4)-antagonist treatment and bone marrow chimeras. SNPs (single-nucleotide polymorphisms) associated with <i>GPR41</i> and <i>GPR43</i> expression were assessed in UK Biobank participants.</p><p><strong>Results: </strong>Untreated GPR41/43KO mice had unaltered blood pressure but had greater cardiac and renal collagen deposition with higher macrophage numbers in the kidney compared with wild-type mice. Ang II-treated GPR41/43KO mice showed higher systolic blood pressure, cardiorenal weights and collagen deposition, and increased gut permeability, which allows the translocation of gastrointestinal bacterial components such as lipopolysaccharides into the circulation. The use of an antagonist to the lipopolysaccharide receptor, TLR4, a potent proinflammatory signaling molecule, restored the cardiovascular phenotype in GPR41/43KO mice. The lack of GPR41/43 expression in the immune compartment was sufficient to lead to a worsened hypertensive phenotype. We also demonstrate that GPR41/43 is, at least partially, responsible for the blood pressure-lowering and cardioprotective effects of a high-fiber diet. Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41 and GPR43 are more prevalent in participants with hypertension.</p><p><strong>Conclusions: </strong>Our findings highlight that lack of short-chain fatty acid-receptor signaling via both GPR41 and GPR43 increases risk of high blood pressure, suggesting treatments that target these receptors could be a novel strategy to prevent or treat hypertension.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e20-e33"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering Platelets: Are They Cells or an Evolved Form of Extracellular Vesicles?","authors":"Eric Boilard, Dylan Burger, Edit Buzas, Paolo Gresele, Kellie R Machlus, Nigel Mackman, Pia Siljander, Rienk Nieuwland","doi":"10.1161/CIRCRESAHA.124.324721","DOIUrl":"10.1161/CIRCRESAHA.124.324721","url":null,"abstract":"<p><p>Platelets are abundant in blood, where they maintain the integrity of the vasculature. Megakaryocytes, the cells responsible for platelet genesis, produce membrane protrusions from which as many as 5000 anucleate platelets can be released into the bloodstream. Platelets lack genomic DNA but contain different molecules, such as RNA, as well as organelles transmitted from the parent megakaryocyte. There is no consensus in the scientific community on whether platelets are cells or not: for example, they are sometimes called cells, small cells, anucleated cells, cell fragments, or megakaryocyte fragments. Extracellular vesicles are particles delimited by a lipid bilayer that are released from cells but cannot replicate on their own. Like platelets, extracellular vesicles lack a nucleus and carry components from their donor cell. Herein, we will explore various viewpoints suggesting that platelets may be cells, albeit not conventional cells, or may be a previously unrecognized type of extracellular vesicle. Beyond a mere debate over terminology, this perspective seeks to help properly define and classify platelets, aiming for better integration into the concept of either cells or extracellular vesicles. This will foster a clearer understanding and drive advances in platelet research.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 4","pages":"442-452"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mineral Stress and Vascular Aging: Decoding the Epigenetic Connection to Slow the Clock.","authors":"Qian Li, Lifang Ye, Jeffrey J Hsu","doi":"10.1161/CIRCRESAHA.125.326064","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.326064","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 4","pages":"400-402"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIPLE Score: GPVI and CD36 Expression Predict a Prothrombotic Platelet Function Phenotype.","authors":"Alexander P Bye, Neline Kriek, Carly Kempster, Joanne L Dunster, Joanne L Mitchell, Tanya Sage, Suzannah Rawlings, Maria V Diaz Alonso, Valentina Shpakova, Abigail Whyte, Leanne Dymott, Sharon Mark, Mark Brunton, Joana Batista, Harriet McKinney, Patrick Thomas, Kate Downes, Amanda J Unsworth, Neil Ruparelia, Charlie McKenna, Chris I Jones, Jonathan M Gibbins","doi":"10.1161/CIRCRESAHA.124.325701","DOIUrl":"10.1161/CIRCRESAHA.124.325701","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"439-441"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental Hypoxia-Induced Ferroptosis Drives Vascular Damage in Preeclampsia.","authors":"Chanho Park, Sruthi Alahari, Jonathan Ausman, Ruizhe Liu, Frederik Nguyen, Julien Sallais, Martin Post, Isabella Caniggia","doi":"10.1161/CIRCRESAHA.124.325119","DOIUrl":"10.1161/CIRCRESAHA.124.325119","url":null,"abstract":"<p><strong>Background: </strong>Iron is an essential micronutrient for cell survival and growth; however, excess of this metal drives ferroptosis. Although maternal iron imbalance and placental hypoxia are independent contributors to the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, the mechanisms by which their interaction impinge on maternal and placental health remain elusive.</p><p><strong>Methods: </strong>We used placentae from normotensive and preeclampsia pregnancy cohorts, human H9 embryonic stem cells differentiated into cytotrophoblast-like cells, and placenta-specific <i>Phd2</i>^<i>-/-</i> preeclamptic mice. Lipid peroxidation and iron cargo of placenta-derived small extracellular vesicles (sEVs) isolated from the maternal circulation of control and preeclampsia individuals were examined by mass spectrometry, flow cytometry, and colorimetry. Human microvascular endothelial cells' angiogenic capacity and function were examined after exposure to control and pathological sEVs.</p><p><strong>Results: </strong>Placentae from preeclampsia pregnancies contain increased ferrous iron and lipid peroxidation byproduct, malondialdehyde. Antioxidant capacity is significantly lower in preeclampsia placentae, with decreased glutathione content, and GPx4 (glutathione peroxidase 4) expression and activity. Hypoxia triggers the occurrence of ferroptosis in human trophoblast cells and mouse <i>Phd2</i>^<i>-</i>^<i>/-</i>placentae. Disrupted placental iron homeostasis in preeclampsia is accompanied by improper extrusion of iron through sEVs mediated by the pentaspan protein prominin-2. Heightened lipid peroxidation content was found in villous explants and maternal circulating sEVs of preeclampsia individuals. Exposure of human microvascular endothelial cells to preeclampsia-derived placental sEVs results in endothelial activation and impaired angiogenesis, which is rescued by treatment with hinokitiol, a compound known to restore tissue iron balance.</p><p><strong>Conclusions: </strong>In pregnancy, iron and oxygen work synergistically to conserve an operative antioxidant system to maintain iron homeostasis and protect the placenta from ferroptotic death. Hindrance to this system due to hypoxia results in heightened ferroptosis rates and sEV-mediated extrusion of harmful lipid peroxides from trophoblast cells into the circulation thereby contributing to maternal endothelial dysfunction characterizing preeclampsia.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"361-378"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000709","DOIUrl":"https://doi.org/10.1161/RES.0000000000000709","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 4","pages":"355-357"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}