Pub Date : 2024-08-30Epub Date: 2024-08-02DOI: 10.1161/CIRCRESAHA.124.324868
Elena Cano, Jennifer Schwarzkopf, Masatoshi Kanda, Eric L Lindberg, Irene Hollfinger, Cristina Pogontke, Caroline Braeuning, Cornelius Fischer, Norbert Hübner, Holger Gerhardt
Background: The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart.
Methods: Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species.
Results: We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. Esm1-lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism.
Conclusions: A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.
{"title":"Intramyocardial Sprouting Tip Cells Specify Coronary Arterialization.","authors":"Elena Cano, Jennifer Schwarzkopf, Masatoshi Kanda, Eric L Lindberg, Irene Hollfinger, Cristina Pogontke, Caroline Braeuning, Cornelius Fischer, Norbert Hübner, Holger Gerhardt","doi":"10.1161/CIRCRESAHA.124.324868","DOIUrl":"10.1161/CIRCRESAHA.124.324868","url":null,"abstract":"<p><strong>Background: </strong>The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart.</p><p><strong>Methods: </strong>Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species.</p><p><strong>Results: </strong>We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. <i>Esm1</i>-lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism.</p><p><strong>Conclusions: </strong>A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874330","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}
Pub Date : 2024-08-30Epub Date: 2024-08-06DOI: 10.1161/CIRCRESAHA.124.324457
Alexander C Bashore, Chenyi Xue, Eunyoung Kim, Hanying Yan, Lucie Y Zhu, Huize Pan, Michael Kissner, Leila S Ross, Hanrui Zhang, Mingyao Li, Muredach P Reilly
Background: Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. They have been identified historically by the cell surface expression of CD14 and CD16. However, recent single-cell studies have revealed that they are much more heterogeneous than previously realized.
Methods: We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing to describe the comprehensive transcriptional and phenotypic landscape of 437 126 monocytes.
Results: This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi (major histocompatibility complex class II), monocyte-platelet aggregates, as well as nonclassical, and several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+ MHCIIhi, CD42b+ monocyte-platelet aggregates, CD16+CD99- nonclassical monocytes, and CD99+ classical monocytes. Each subpopulation exhibited unique characteristics, developmental trajectories, transcriptional regulation, and tissue distribution. In addition, alterations associated with cardiovascular disease risk factors, including race, smoking, and hyperlipidemia were identified. Moreover, the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol.
Conclusions: This integrative and cross-species comparative analysis provides a new perspective on the comparison of alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in cardiovascular disease and the potential for monocyte subpopulation targeted therapies.
背景:单核细胞是一种重要的先天性免疫系统细胞类型,具有平衡和免疫调节功能。历史上,人们通过细胞表面 CD14 和 CD16 的表达来识别它们。然而,最近的单细胞研究发现,它们的异质性比以前认识到的要大得多:我们利用细胞转录组索引和表位测序(cellular indexing of transcriptomes and epitopes by sequencing)以及单细胞 RNA 测序来描述 437 126 个单核细胞的全面转录和表型图谱:结果:这一高维多模式方法发现了大量表型多样性和功能独特的亚群,包括 IFN 反应性、MHCIIhi、单核细胞-血小板聚集以及非经典单核细胞、经典单核细胞的几个亚群。通过流式细胞术,我们验证了 MHCII+CD275+ MHCIIhi、CD42b+ 单核细胞-血小板聚集体、CD16+CD99- 非典型单核细胞和 CD99+ 经典单核细胞的存在。每个亚群都表现出独特的特征、发育轨迹、转录调控和组织分布。此外,还发现了与心血管疾病风险因素(包括种族、吸烟和高脂血症)相关的改变。此外,在胆固醇升高的小鼠模型中重现了高脂血症的影响:这项综合的跨物种比较分析为比较病理条件下单核细胞的改变提供了一个新的视角,并为了解心血管疾病中单核细胞驱动机制以及单核细胞亚群靶向疗法的潜力提供了见解。
{"title":"Monocyte Single-Cell Multimodal Profiling in Cardiovascular Disease Risk States.","authors":"Alexander C Bashore, Chenyi Xue, Eunyoung Kim, Hanying Yan, Lucie Y Zhu, Huize Pan, Michael Kissner, Leila S Ross, Hanrui Zhang, Mingyao Li, Muredach P Reilly","doi":"10.1161/CIRCRESAHA.124.324457","DOIUrl":"10.1161/CIRCRESAHA.124.324457","url":null,"abstract":"<p><strong>Background: </strong>Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. They have been identified historically by the cell surface expression of CD14 and CD16. However, recent single-cell studies have revealed that they are much more heterogeneous than previously realized.</p><p><strong>Methods: </strong>We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing to describe the comprehensive transcriptional and phenotypic landscape of 437 126 monocytes.</p><p><strong>Results: </strong>This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCII<sup>hi</sup> (major histocompatibility complex class II), monocyte-platelet aggregates, as well as nonclassical, and several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII<sup>+</sup>CD275<sup>+</sup> MHCII<sup>hi</sup>, CD42b<sup>+</sup> monocyte-platelet aggregates, CD16<sup>+</sup>CD99<sup>-</sup> nonclassical monocytes, and CD99<sup>+</sup> classical monocytes. Each subpopulation exhibited unique characteristics, developmental trajectories, transcriptional regulation, and tissue distribution. In addition, alterations associated with cardiovascular disease risk factors, including race, smoking, and hyperlipidemia were identified. Moreover, the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol.</p><p><strong>Conclusions: </strong>This integrative and cross-species comparative analysis provides a new perspective on the comparison of alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in cardiovascular disease and the potential for monocyte subpopulation targeted therapies.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892994","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}
Pub Date : 2024-08-30Epub Date: 2024-07-31DOI: 10.1161/CIRCRESAHA.124.324924
Jiahui Ge, Yingbi Zhou, Hui Li, Ruhui Zeng, Kaiqi Xie, Jing Leng, Xijian Chen, Gang Yu, Xinya Shi, Yineng Xu, Dong He, Pi Guo, Yongyin Zhou, Hongjun Luo, Wenhong Luo, Bin Liu
<p><strong>Background: </strong>Prostaglandin I<sub>2</sub> synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I<sub>2</sub> production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I<sub>2</sub> synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.</p><p><strong>Methods: </strong>Experiments were performed with wild-type, <i>Pgis</i> knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup>) and <i>Pgis</i>/thromboxane-prostanoid receptor gene (<i>Tp</i>) double knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup><i>Tp</i><sup><i>-</i>/<i>-</i></sup>) mice and <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice transplanted with unfractionated wild-type or <i>Cox-1</i><sup><i>-</i>/<i>-</i></sup> bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.</p><p><strong>Results: </strong>PGF<sub>2α</sub>, PGE<sub>2</sub>, and a trace amount of PGD<sub>2</sub>, but not thromboxane A<sub>2</sub> (TxA<sub>2</sub>), were produced in response to acetylcholine in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> aortas. <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA<sub>2</sub> receptor) not only restrained EDC and the downregulation of NO signaling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice but also ameliorated the cardiovascular abnormalities. Stimulation of <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> vessels with acetylcholine in the presence of platelets led to increased TxA<sub>2</sub> generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice though it largely suppressed the increase of plasma TxB<sub>2</sub> (TxA<sub>2</sub> metabolite) level.</p><p><strong>Conclusions: </strong>Our study demonstrates that the non-TxA<sub>2</sub> prostanoids/T
{"title":"Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA<sub>2</sub> Prostanoids/TP Axis.","authors":"Jiahui Ge, Yingbi Zhou, Hui Li, Ruhui Zeng, Kaiqi Xie, Jing Leng, Xijian Chen, Gang Yu, Xinya Shi, Yineng Xu, Dong He, Pi Guo, Yongyin Zhou, Hongjun Luo, Wenhong Luo, Bin Liu","doi":"10.1161/CIRCRESAHA.124.324924","DOIUrl":"10.1161/CIRCRESAHA.124.324924","url":null,"abstract":"<p><strong>Background: </strong>Prostaglandin I<sub>2</sub> synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I<sub>2</sub> production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I<sub>2</sub> synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.</p><p><strong>Methods: </strong>Experiments were performed with wild-type, <i>Pgis</i> knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup>) and <i>Pgis</i>/thromboxane-prostanoid receptor gene (<i>Tp</i>) double knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup><i>Tp</i><sup><i>-</i>/<i>-</i></sup>) mice and <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice transplanted with unfractionated wild-type or <i>Cox-1</i><sup><i>-</i>/<i>-</i></sup> bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.</p><p><strong>Results: </strong>PGF<sub>2α</sub>, PGE<sub>2</sub>, and a trace amount of PGD<sub>2</sub>, but not thromboxane A<sub>2</sub> (TxA<sub>2</sub>), were produced in response to acetylcholine in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> aortas. <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA<sub>2</sub> receptor) not only restrained EDC and the downregulation of NO signaling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice but also ameliorated the cardiovascular abnormalities. Stimulation of <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> vessels with acetylcholine in the presence of platelets led to increased TxA<sub>2</sub> generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice though it largely suppressed the increase of plasma TxB<sub>2</sub> (TxA<sub>2</sub> metabolite) level.</p><p><strong>Conclusions: </strong>Our study demonstrates that the non-TxA<sub>2</sub> prostanoids/T","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855002","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}
Pub Date : 2024-08-30Epub Date: 2024-08-29DOI: 10.1161/CIRCRESAHA.124.325195
Julio Silva-Neto, Walter J Koch
{"title":"A New Piece to the AMPK Puzzle in Heart Repair: Phosphorylation of β-Arrestin-1.","authors":"Julio Silva-Neto, Walter J Koch","doi":"10.1161/CIRCRESAHA.124.325195","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325195","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104846","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}
Pub Date : 2024-08-30Epub Date: 2024-08-29DOI: 10.1161/CIRCRESAHA.124.325134
Catherine C Hedrick
{"title":"Single-Cell Sleuthing: Cracking the Monocyte Code for Cardiovascular Clues.","authors":"Catherine C Hedrick","doi":"10.1161/CIRCRESAHA.124.325134","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325134","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104848","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}
Pub Date : 2024-08-30Epub Date: 2024-08-29DOI: 10.1161/RES.0000000000000690
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000690","DOIUrl":"https://doi.org/10.1161/RES.0000000000000690","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104847","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}
Pub Date : 2024-08-30Epub Date: 2024-07-29DOI: 10.1161/CIRCRESAHA.124.324272
Khaled Z Abd-Elmoniem, Jehad H Edwan, Katrina B Dietsche, Alfredo Villalobos-Perez, Nour Shams, Jatin Matta, Leilah Baumgarten, Waleed N Qaddumi, Sydney A Dixon, Aruba Chowdhury, Michael Stagliano, Lilian Mabundo, Annemarie Wentzel, Colleen Hadigan, Ahmed M Gharib, Stephanie T Chung
Background: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.
Methods: Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.
Results: Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.
Conclusions: Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.
{"title":"Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.","authors":"Khaled Z Abd-Elmoniem, Jehad H Edwan, Katrina B Dietsche, Alfredo Villalobos-Perez, Nour Shams, Jatin Matta, Leilah Baumgarten, Waleed N Qaddumi, Sydney A Dixon, Aruba Chowdhury, Michael Stagliano, Lilian Mabundo, Annemarie Wentzel, Colleen Hadigan, Ahmed M Gharib, Stephanie T Chung","doi":"10.1161/CIRCRESAHA.124.324272","DOIUrl":"10.1161/CIRCRESAHA.124.324272","url":null,"abstract":"<p><strong>Background: </strong>Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.</p><p><strong>Methods: </strong>Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.</p><p><strong>Results: </strong>Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; <i>P</i>=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; <i>P</i><0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; <i>P</i>=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.</p><p><strong>Conclusions: </strong>Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787368","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}
Pub Date : 2024-08-29DOI: 10.1161/CIRCRESAHA.124.324829
Stefano Strocchi, Luo Liu, Rongling Wang, Steffen P Häseli, Federico Capone, David Bode, Natasha Nambiar, Tolga Eroglu, Leandro Santiago Padilla, Catherine Farrelly, Antonio Vacca, Marianna Mascagni, Christian U Oeing, Ulrich Kintscher, Simone Jung, Saskia A Diezel, Sarah V Liévano Contreras, Mingqi Zhou, Marcus Seldin, Gabriele G Schiattarella
{"title":"Systems Biology Approach Uncovers Candidates for Liver-Heart Interorgan Crosstalk in HFpEF.","authors":"Stefano Strocchi, Luo Liu, Rongling Wang, Steffen P Häseli, Federico Capone, David Bode, Natasha Nambiar, Tolga Eroglu, Leandro Santiago Padilla, Catherine Farrelly, Antonio Vacca, Marianna Mascagni, Christian U Oeing, Ulrich Kintscher, Simone Jung, Saskia A Diezel, Sarah V Liévano Contreras, Mingqi Zhou, Marcus Seldin, Gabriele G Schiattarella","doi":"10.1161/CIRCRESAHA.124.324829","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.324829","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104845","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}
Pub Date : 2024-08-23DOI: 10.1161/CIRCRESAHA.124.324722
Qingqing Chu, Yujia Li, Jichao Wu, Yanjiao Gao, Xiangyun Guo, Jing Li, Hang Lv, Min Liu, Wei Tang, Peng Zhan, Tao Zhang, Huili Hu, Hong Liu, Jinpeng Sun, Xiaojie Wang, Fan Yi
Background: Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown.
Methods: Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study.
Results: Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice.
Conclusions: This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.
{"title":"Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.","authors":"Qingqing Chu, Yujia Li, Jichao Wu, Yanjiao Gao, Xiangyun Guo, Jing Li, Hang Lv, Min Liu, Wei Tang, Peng Zhan, Tao Zhang, Huili Hu, Hong Liu, Jinpeng Sun, Xiaojie Wang, Fan Yi","doi":"10.1161/CIRCRESAHA.124.324722","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.324722","url":null,"abstract":"<p><strong>Background: </strong>Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown.</p><p><strong>Methods: </strong>Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study.</p><p><strong>Results: </strong>Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice.</p><p><strong>Conclusions: </strong>This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035419","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}