Alcohol Regulation of Endothelial Plasticity in Atherosclerosis

酒精对动脉粥样硬化内皮可塑性的调节

基本信息

批准号：
10585070
负责人：
EILEEN M. REDMOND
金额：
$ 5.53万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10585070
关键词：
Affect Alcohol consumption Alcohols Antiatherogenic Area Arterial Fatty Streak Arteriosclerosis Atherosclerosis Basic Science Biological Models Blood Vessels Blood flow Cardiovascular Diseases Cause of Death Cell Culture Techniques Cells Cessation of life Chronic Clinical Computer Analysis Consumption Data Development Dose Endothelial Cells Endothelium Ethanol Exposure to Guidelines Homeostasis Human Hyperplasia Hypoxia In Vitro Incidence Inflammatory Knowledge Laboratory Study Lesion Lipids Medial Mediating Mesenchymal Modeling Molecular Myocardial Infarction Myofibroblast Pathogenicity Pathologic Pathology Pattern Phenotype Population Prevention Process Proliferating Published Comment Publishing RNA Computations Regulation Reporting Research Role Science Severities Shapes Signal Transduction Smooth Muscle Myocytes Stimulus Stroke Target Populations Testing Transforming Growth Factor beta Transgenic Mice Vascular Endothelial Cell Vascular Smooth Muscle Woman alcohol effect antagonist arterial stiffness binge drinking cardiovascular disorder therapy cardiovascular health cytokine disability drinking drinking behavior epidemiology study innovation interest intimal medial thickening men migration mimetics modifiable behavior mouse model notch protein novel novel therapeutics physiologic model prevent problem drinker protective effect response single-cell RNA sequencing transcriptomics transdifferentiation

Affect Alcohol consumption Alcohols Antiatherogenic Area Arterial Fatty Streak Arteriosclerosis Atherosclerosis Basic Science Biological Models Blood Vessels Blood flow Cardiovascular Diseases Cause of Death Cell Culture Techniques Cells Cessation of life Chronic Clinical Computer Analysis Consumption Data Development Dose Endothelial Cells Endothelium Ethanol Exposure to Guidelines Homeostasis Human Hyperplasia Hypoxia In Vitro Incidence Inflammatory Knowledge Laboratory Study Lesion Lipids Medial Mediating Mesenchymal Modeling Molecular Myocardial Infarction Myofibroblast Pathogenicity Pathologic Pathology Pattern Phenotype Population Prevention Process Proliferating Published Comment Publishing RNA Computations Regulation Reporting Research Role Science Severities Shapes Signal Transduction Smooth Muscle Myocytes Stimulus Stroke Target Populations Testing Transforming Growth Factor beta Transgenic Mice Vascular Endothelial Cell Vascular Smooth Muscle Woman alcohol effect antagonist arterial stiffness binge drinking cardiovascular disorder therapy cardiovascular health cytokine disability drinking drinking behavior epidemiology study innovation interest intimal medial thickening men migration mimetics modifiable behavior mouse model notch protein novel novel therapeutics physiologic model prevent problem drinker protective effect response single-cell RNA sequencing transcriptomics transdifferentiation

展开

项目摘要

Abstract Cardiovascular disease is the leading cause of death globally. Studies show that low-to-moderate alcohol consumption is protective against cardiovascular disease, whereas heavy binge drinking and chronic abuse is harmful. Currently lacking, however, is in-depth knowledge of the mechanisms involved. In particular, understanding the cell and molecular processes mediating the protective effects of alcohol is of great interest and could lead to novel therapies for cardiovascular disease. Most of the problems associated with cardiovascular disease are caused by arteriosclerosis, a thickening and stiffening of artery walls, that may lead to blood flow blockage resulting in heart attack or stroke. Arteriosclerosis develops in areas where the endothelial lining becomes activated or damaged in response to injurious stimuli. Emerging evidence suggests that endothelial cells, by undergoing a change in phenotype to a myofibroblast in a process known as endothelial-to-mesenchymal transition (EndMT), may themselves be key drivers of arteriosclerosis. This raises the exciting possibility of a novel cell mechanism involved in vascular pathology. Crucially, no information exists as to whether alcohol, a known modulator of cardiovascular disease, might regulate EndMT in this context, a question of considerable interest and the focus of our exploratory proposal. We have previously reported that daily moderate alcohol (EtOH) consumption reduces arteriosclerosis, while heavy binge consumption worsens it, and that EtOH stimulates Notch signaling in vascular endothelial cells. Our recently published study and our preliminary data demonstrate that EtOH at moderate levels acts to maintain endothelium in a beneficial ‘non-activated’ state. Moreover, our preliminary data are suggestive of a j- shaped relationship between EtOH and transforming growth factor-beta (TGFb)-induced EndMT of arterial endothelial cells, with lower doses of EtOH inhibiting and higher doses stimulating EC transition. Thus, the overall hypothesis of our proposal is that low-moderate alcohol consumption prevents endothelial activation, limiting EndMT in a Notch-dependent manner, thus, maintaining vessel homeostasis and protecting against arteriosclerosis, whereas binge drinking increases endothelial activation resulting in greater EndMT and exacerbated lesions. We will use human endothelial cells exposed to atherogenic stimuli in vitro, in combination with single cell RNA-sequencing (scRNA-seq) analyses of endothelial cells from a mouse model of arteriosclerosis to test our hypothesis and elucidate the mechanisms involved. Our novel study will illuminate how ‘healthy’ and ‘harmful’ alcohol consumption differentially impacts arteriosclerosis by affecting endothelial cell plasticity. These data potentially have important clinical implications with regard to prevention, treatment, and regression of cardiovascular disease.

抽象的心血管疾病是全球死亡的主要原因。研究表明，低到中度酒精消费受到保护免受心血管疾病的保护有害。但是，目前缺乏对所涉及机制的深入了解。尤其，了解介导酒精受保护作用的细胞和分子过程引起了极大的关注并可能导致新的心血管疾病疗法。与心血管疾病相关的大多数问题是由动脉硬化引起的，这是增厚动脉壁的僵硬，可能导致血液流动阻塞，导致心脏病发作或中风。动脉硬化发生在内皮衬里因响应而被激活或受损的地区有害刺激。新兴的证据表明，通过经历表型的变化为A的内皮细胞在称为内皮到间质转变（ENDMT）的过程中，肌纤维细胞本身可能是关键动脉硬化的驱动因素。这增加了涉及血管的新细胞机制的激动人心的可能性病理。 con依的是，尚无关于酒精是否已知的心血管疾病调节剂的信息，在这种情况下，可能会规范EndMT，这是一个考虑问题和我们探索性的重点提议。我们以前已经报道说，每日现代酒精（ETOH）消费减少了动脉硬化，虽然大暴饮暴食使它恶化，而EtOH刺激了血管内皮中的Notch信号传导细胞。我们最近发表的研究和初步数据表明，中等水平的eTOH起作用将内皮保持在有益的“非激活”状态下。此外，我们的初步数据暗示了J- ETOH与转化生长因子-Beta（TGFB）诱导的动脉末端之间的形状关系内皮细胞，较低剂量的EtOH抑制和较高剂量的EC转变。这是我们提议的总体假设是低温饮酒可防止内皮激活，以缺口依赖的方式限制EndMT，因此保持血管稳态和预防动脉硬化，而暴饮暴食会增加内皮激活，从而增加 Endmt和恶化的病变。我们将在体外使用暴露于动脉粥样硬化刺激的人内皮细胞，与单个细胞RNA-requencing（SCRNA-SEQ）组合对内皮细胞的分析，来自小鼠模型动脉硬化以检验我们的假设并阐明所涉及的机制。我们的新颖研究将阐明 “健康”和“有害”的饮酒如何通过影响内皮来影响动脉硬化。细胞塑性。这些数据可能在预防，治疗方面具有重要的临床意义和心血管疾病的回归。