Alcohol Regulation of Endothelial Plasticity in Atherosclerosis

摘要 心血管疾病是全球主要的死亡原因。研究表明，低度至中度酒精 饮酒可以预防心血管疾病，而酗酒和慢性滥用则可以预防心血管疾病。 有害然而，目前缺乏对所涉机制的深入了解。特别是， 了解细胞和分子过程介导的保护作用的酒精是非常感兴趣的 并可能导致心血管疾病的新疗法。 大多数与心血管疾病相关的问题是由动脉硬化引起的， 以及动脉壁变硬，这可能导致血流阻塞，从而导致心脏病发作或中风。 动脉炎发生在内皮细胞衬里被激活或受损的区域， 有害的刺激。新出现的证据表明，内皮细胞，通过经历表型的变化， 肌成纤维细胞在一个被称为内皮-间质转化（EndMT）的过程中， 动脉硬化的驱动因素。这提出了一种令人兴奋的可能性，即一种新的细胞机制参与血管内皮细胞的生长。 病理至关重要的是，没有信息表明酒精，一种已知的心血管疾病的调节剂， 在这种情况下，我们可能会监管EndMT，这是一个相当感兴趣的问题，也是我们探索的重点。 提议 我们以前曾报道过，每日适量饮酒（EtOH）可减少动脉硬化， 而大量的暴饮暴食则会使其恶化，EtOH会刺激血管内皮细胞中的Notch信号传导， 细胞我们最近发表的研究和我们的初步数据表明，乙醇在中等水平的行为， 维持内皮处于有益的“非活化”状态。此外，我们的初步数据表明，一个j- EtOH与转化生长因子β（TGF β）诱导的动脉EndMT之间的形状关系 内皮细胞，低剂量EtOH抑制和高剂量刺激EC转换。 因此，我们建议的总体假设是，低中度饮酒可以预防 内皮激活，以Notch依赖性方式限制EndMT，从而维持血管稳态， 防止动脉硬化，而狂饮增加内皮激活，导致更大的 EndMT和恶化的病变。我们将在体外使用暴露于致动脉粥样硬化刺激的人内皮细胞， 与来自血管内皮细胞瘤小鼠模型的内皮细胞的单细胞RNA测序（scRNA-seq）分析组合， 动脉硬化来验证我们的假设并阐明相关机制。我们的新研究将阐明 “健康”和“有害”的酒精消费如何通过影响内皮细胞而不同地影响动脉硬化 细胞可塑性这些数据可能在预防、治疗、 和心血管疾病的消退。

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.