Circulation research最新文献

{"title":"Micro RNA Regulating a Mega Difference in Male and Female Cardiac Physiology.","authors":"Wyatt G Paltzer, James F Martin","doi":"10.1161/CIRCRESAHA.124.325941","DOIUrl":"10.1161/CIRCRESAHA.124.325941","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 3","pages":"276-278"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063992","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":"Non-Canonical TERT Activity Initiates Osteogenesis in Calcific Aortic Valve Disease.","authors":"Rolando A Cuevas,Luis Hortells,Claire C Chu,Ryan Wong,Alex Crane,Camille Boufford,Cailyn Regan,William J Moorhead Iii,Michael J Bashline,Aneesha Parwal,Angelina M Parise,Parya Behzadi,Mark J Brown,Aditi Gurkar,Dennis Bruemmer,John Sembrat,Ibrahim Sultan,Thomas G Gleason,Marie Billaud,Cynthia St Hilaire","doi":"10.1161/circresaha.122.321889","DOIUrl":"https://doi.org/10.1161/circresaha.122.321889","url":null,"abstract":"BACKGROUNDCalcific aortic valve disease is the pathological remodeling of valve leaflets. The initial steps in valve leaflet osteogenic reprogramming are not fully understood. As TERT (telomerase reverse transcriptase) overexpression primes mesenchymal stem cells to differentiate into osteoblasts, we investigated whether TERT contributes to the osteogenic reprogramming of valve interstitial cells.METHODSHuman control and calcific aortic valve disease aortic valve leaflets and patient-specific human aortic valve interstitial cells were used in in vivo and in vitro calcification assays. Loss of function experiments in human aortic valve interstitial cells and cells isolated from Tert-/- and Terc-/- mice were used for mechanistic studies. Calcification was assessed in Tert+/+ and Tert-/- mice ex vivo and in vivo. In silico modeling, proximity ligation, and coimmunoprecipitation assays defined novel TERT interacting partners. Chromatin immunoprecipitation and cleavage under targets and tagmentation sequencing defined protein-DNA interactions.RESULTSTERT protein was highly expressed in calcified valve leaflets without changes in telomere length, DNA damage, or senescence markers, and these features were retained in isolated primary human aortic valve interstitial cells. TERT expression increased with osteogenic or inflammatory stimuli, and knockdown or genetic deletion of TERT prevented calcification in vitro and in vivo. Mechanistically, TERT was upregulated via NF-κB and required to initiate osteogenic reprogramming, independent of its canonical reverse transcriptase activity and the long noncoding RNA TERC. TERT exerts noncanonical osteogenic functions via binding with STAT5 (signal transducer and activator of transcription 5). Depletion or inhibition of STAT5 prevented calcification. STAT5 was found to bind the promoter region of RUNX2 (runt-related transcription factor 2), the master regulator of osteogenic reprogramming. Finally, we demonstrate that TERT and STAT5 are upregulated and colocalized in calcific aortic valve disease tissue compared with control tissue.CONCLUSIONSTERT's noncanonical activity is required to initiate calcification. TERT is upregulated via inflammatory signaling pathways and partners with STAT5 to bind the RUNX2 gene promoter. These data identify a novel mechanism and potential therapeutic target to decrease vascular calcification.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"74 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991659","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":"ACKR1^hiECs Promote Aortic Dissection Through Adjusting Macrophage Behavior.","authors":"Yayu Wang, Xiong Jia, Yifei Zhang, Bin Zhang, Yazhe Zhou, Xiaoru Li, Xiaoying Zhu, Jinquan Xia, Jun Ren, Chang Zou, Qijun Zheng","doi":"10.1161/CIRCRESAHA.124.325458","DOIUrl":"10.1161/CIRCRESAHA.124.325458","url":null,"abstract":"<p><strong>Background: </strong>Type A aortic dissection (TAAD) is a life-threatening condition characterized by complex pathophysiology, in which macrophages play a critical but not yet fully understood role. This study focused on the role of endothelial cells with elevated expression of ACKR1 (atypical chemokine receptor 1) and their interaction with proinflammatory macrophages in TAAD development.</p><p><strong>Methods: </strong>Single-cell transcriptomic analysis of human aortic tissues was used to identify cellular heterogeneity in TAAD. Clinical and animal studies evaluated the relationship between ACKR1 expression and TAAD severity. Gain- and loss-of-function experiments, involving modulation of ACKR1 expression in ECs, investigated its role in macrophage regulation. Molecular docking and in vitro/in vivo studies identified and tested potential drugs targeting ACKR1.</p><p><strong>Results: </strong>TAAD tissues exhibited increased ECs with high ACKR1 expression and proinflammatory macrophages. High ACKR1 levels were strongly associated with TAAD severity. Knockdown of ACKR1 suppressed the NF-κB (nuclear factor-κB) signaling pathway and SPP1 (secreted phosphoprotein 1) expression, reducing macrophage migration and polarization, thereby inhibiting TAAD progression. Conversely, overexpression of ACKR1 exacerbated TAAD. Amikacin, identified as an ACKR1 targeted drug, regulated macrophage behavior via the ACKR1/NF-κB/SPP1 pathway, attenuating TAAD progression and improving survival in mice.</p><p><strong>Conclusions: </strong>This study reveals how endothelial cells exhibiting high ACKR1 expression modulate macrophage migration and proinflammatory polarization through the ACKR1/NF-κB/SPP1 signaling pathway, a crucial mechanism in TAAD progression. Targeting ACKR1 through both functional and pharmacological approaches effectively suppressed TAAD progression and extended survival in TAAD mice, offering promising new intervention strategies for clinical evaluation.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"211-228"},"PeriodicalIF":16.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845855","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":"Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension.","authors":"Yandong Pei, Dongfeng Ren, Yuanhao Yin, Jiajia Shi, Qianyuan Ai, Wenxin Hao, Xiaofan Luo, Chenyue Zhang, Yanping Zhao, Chenyu Bai, Lin Zhu, Qiong Wang, Shuangling Li, Yuwei Zhang, Jiangtao Lu, Lin Liu, Lin Zhou, Yuli Wu, Yiqi Weng, Yongle Jing, Chengzhi Lu, Yujie Cui, Hao Zheng, Yanjun Li, Guo Chen, Gang Hu, Quan Chen, Xudong Liao","doi":"10.1161/CIRCRESAHA.124.325156","DOIUrl":"10.1161/CIRCRESAHA.124.325156","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is associated with endothelial dysfunction. However, the cause of endothelial dysfunction and its impact on PH remain incompletely understood. We aimed to investigate whether the hypoxia-inducible FUNDC1 (FUN14 domain-containing 1)-dependent mitophagy pathway underlies PH pathogenesis and progression.</p><p><strong>Methods: </strong>We first analyzed FUNDC1 protein levels in lung samples from patients with PH and animal models. Using rodent PH models induced by HySu (hypoxia+SU5416) or chronic hypoxia, we further investigated PH pathogenesis and development in response to global and cell-type-specific <i>Fundc1</i> loss/gain-of-function. We also investigated the spontaneous PH in mice with inducible loss of endothelial <i>Fundc1</i>. In addition, histological, metabolic, and transcriptomic studies were performed to delineate molecular mechanisms. Finally, findings were validated in vivo by compound deficiency of HIF2α (hypoxia-inducible factor 2α; <i>Epas1</i>) and pharmacological intervention.</p><p><strong>Results: </strong>FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global <i>Fundc1</i> deficiency exacerbated PH, while its overexpression was protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial <i>Fundc1</i> in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial <i>Fundc1</i> protected against PH before and after the onset of disease. Mechanistically, <i>Fundc1</i> deficiency impaired basal mitophagy in endothelial cells, leading to the accumulation of dysfunctional mitochondria, metabolic reprogramming toward aerobic glycolysis, pseudohypoxia, and senescence, likely via a mtROS-HIF2α signaling pathway. Subsequently, <i>Fundc1</i>-deficient endothelial cells increased IGFBP2 (insulin-like growth factor-binding protein 2) secretion that drove pulmonary arterial remodeling to instigate PH. Finally, proof-of-principle in vivo studies showed significant efficacy on PH amelioration by targeting endothelial mitophagy, pseudohypoxia, senescence, or IGFBP2.</p><p><strong>Conclusions: </strong>Collectively, we show that FUNDC1-mediated basal mitophagy is critical for endothelial homeostasis, and its disruption instigates PH pathogenesis. Given that similar changes in FUNDC1 and IGFBP2 were observed in PH patients, our findings are of significant clinical relevance and provide novel therapeutic strategies for PH.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e1-e19"},"PeriodicalIF":16.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799625","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":"Follistatin From hiPSC-Cardiomyocytes Promotes Myocyte Proliferation in Pigs With Postinfarction LV Remodeling.","authors":"Yuhua Wei, Gregory Walcott, Thanh Nguyen, Xiaoxiao Geng, Bijay Guragain, Hanyu Zhang, Akazha Green, Manuel Rosa-Garrido, Jack M Rogers, Daniel J Garry, Lei Ye, Jianyi Zhang","doi":"10.1161/CIRCRESAHA.124.325562","DOIUrl":"10.1161/CIRCRESAHA.124.325562","url":null,"abstract":"<p><strong>Background: </strong>When human induced pluripotent stem cells (hiPSCs) that CCND2-OE (overexpressed cyclin-D2) were differentiated into cardiomyocytes (^CCND2-OEhiPSC-CMs) and administered to the infarcted hearts of immunodeficient mice, the cells proliferated after administration and repopulated >50% of the scar. Here, we knocked out human leukocyte antigen class I and class II expression in ^CCND2-OEhiPSC-CMs (^KO/OEhiPSC-CMs) to reduce the cells' immunogenicity and then assessed the therapeutic efficacy of ^KO/OEhiPSC-CMs for the treatment of myocardial infarction.</p><p><strong>Methods: </strong>^KO/OEhiPSC-CM and wild-type hiPSC-CM (^WThiPSC-CM) spheroids were differentiated in shaking flasks, purified, characterized, and intramyocardially injected into pigs after ischemia/reperfusion injury; control animals were injected with basal medium. Cardiac function was evaluated via cardiac magnetic resonance imaging, and cardiomyocyte proliferation was assessed via immunostaining and single-nucleus RNA sequencing.</p><p><strong>Results: </strong>Measurements of cardiac function and scar size were significantly better in pigs treated with ^KO/OEhiPSC-CM spheroids than in animals treated with medium or ^WThiPSC-CM spheroids. ^KO/OEhiPSC-CMs were detected for just 1 week after administration, but assessments of cell cycle activity and proliferation were significantly higher in the endogenous pig cardiomyocytes of the hearts from the ^KO/OEhiPSC-CM spheroid group than in those from the other 2 groups. Single-nucleus RNA-sequencing analysis identified a cluster of proliferating cardiomyocytes that was significantly more prevalent in the ^KO/OEhiPSC-CM spheroid-treated hearts (3.65%) than in the hearts from the medium (0.89%) or ^WThiPSC-CM spheroid (1.33%) groups at week 1. YAP (Yes-associated protein) protein levels and nuclear localization were also significantly upregulated in pig cardiomyocytes after treatment with ^KO/OEhiPSC-CM spheroids. Follistatin, which interacts with the HIPPO/YAP pathway, was significantly more abundant in the medium from ^KO/OEhiPSC-CM spheroids than ^WThiPSC-CM spheroids (30.29±2.39 versus 16.62±0.83 ng/mL, <i>P</i>=0.0056). Treatment with follistatin increased ^WThiPSC-CM cell counts by 28.3% over 16 days in culture and promoted cardiomyocyte proliferation in the infarcted hearts of adult mice.</p><p><strong>Conclusions: </strong>^KO/OEhiPSC-CM spheroids significantly improved cardiac function and reduced infarct size in pig hearts after ischemia/reperfusion injury by secreting follistatin, which upregulated HIPPO/YAP signaling and proliferation in endogenous pig cardiomyocytes.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"161-176"},"PeriodicalIF":16.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845859","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":"SGLT2 Inhibition Induces Cardioprotection by Increasing Parasympathetic Activity.","authors":"Maryna V Basalay, Alla Korsak, Zhenhe He, Alexander V Gourine, Sean M Davidson, Derek M Yellon","doi":"10.1161/CIRCRESAHA.124.324708","DOIUrl":"10.1161/CIRCRESAHA.124.324708","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"229-231"},"PeriodicalIF":16.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845861","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":"ET-3/ETBR Mediates Na⁺-Activated Immune Signaling and Kidney Lymphatic Dynamics.","authors":"Ashley L Mutchler, Jianyong Zhong, Hai-Chun Yang, Shilin Zhao, Rachelle Crescenzi, Shannon Taylor, Roy L Rao, Elaine L Shelton, Annet Kirabo, Valentina Kon","doi":"10.1161/CIRCRESAHA.124.324890","DOIUrl":"10.1161/CIRCRESAHA.124.324890","url":null,"abstract":"<p><strong>Background: </strong>Lymphatic collecting vessels in the kidney are critical in clearing interstitial fluid, macromolecules, and infiltrating immune cells. Dysfunction of the lymphatic vessels can disrupt this process and exacerbate injury-associated inflammation in many disease conditions. We previously found that sodium accumulates within the kidney interstitium during proteinuric kidney injury and elevated sodium environments stimulate isolevuglandin production in antigen-presenting cells, stimulating T cells, and modulating inflammatory responses. In the present study, we investigated whether proteinuric injury increases production of isolevuglandin-adduct formation in antigen-presenting cells, their effects on lymphatic endothelial cells (LECs), and the role of the ET-3 (endothelin-3)/ETBR (endothelin type B receptor) on lymphatic vessel function.</p><p><strong>Methods: </strong>We used a mouse model of nephrotoxin-induced proteinuric injury to show that proteinuric injury expanded the kidney lymphatic network and to immunophenotype the infiltrating immune cells. To determine mechanisms, we analyzed the interaction of migratory immune cells and LECs using an in vitro transwell migration assay, bulk RNA sequencing, and flow cytometric analysis. To determine the effect of ET-3/ETBR axis on lymphatic vessel contractility, we analyzed microdissected lymphangions utilizing a vessel perfusion chamber.</p><p><strong>Results: </strong>We found that animals with proteinuric injury have increased kidney lymphangiogenesis, isolevuglandin-producing dendritic cells, and IFN (interferon)-γ-producing CD4+T cells. The sodium avid environment present in kidney injury enhances the interaction between LECs and migratory antigen-presenting cells and LEC production of isolevuglandin-adducts. Elevated sodium environment-induced isolevuglandin-adduct formation facilitates the ET-3/ETBR communication between LECs and dendritic cells. In addition, the ET-3/ETBR axis modulates lymphatic collecting vessel pumping dynamics.</p><p><strong>Conclusions: </strong>These findings reveal a novel mechanism linking the isolevuglandin-mediated ET-3/ETBR axis with LECs and infiltrating dendritic cells. ET-3/ETBR signaling in lymphatic vessel dynamics is a novel pathogenic component and a possible therapeutic target in kidney disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"194-208"},"PeriodicalIF":16.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827507","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000707","DOIUrl":"https://doi.org/10.1161/RES.0000000000000707","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 2","pages":"159-160"},"PeriodicalIF":16.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000797","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":"Endothelial METAP1: Tipping the Angiogenic Scales in Postpartum Preeclampsia.","authors":"Jessica L Faulkner,Matthew R Alexander","doi":"10.1161/circresaha.124.325503","DOIUrl":"https://doi.org/10.1161/circresaha.124.325503","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"23 1","pages":"191-193"},"PeriodicalIF":20.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988724","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":"ABE-Mediated Cardiac Gene Silencing via Single AAVs Requires DNA Accessibility.","authors":"Zhanzhao Liu,Luzi Yang,Yuhan Yang,Jiting Li,Zhan Chen,Congting Guo,Qianhao Guo,Qiuxuan Li,Dongyu Zhao,Xiaomin Hu,Fei Gao,Yuxuan Guo","doi":"10.1161/circresaha.124.325611","DOIUrl":"https://doi.org/10.1161/circresaha.124.325611","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"8 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988721","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}