Klotho and the pathogenesis of cardiovascular disease

描述(申请人提供)：心血管疾病是西方国家发病率和死亡率的主要原因。尽管医学在识别可改变的心血管危险因素方面取得了实质性进展，但相当大比例的心血管疾病患者 疾病没有已知的风险因素。Klotho是一种新近发现的激素，可以预防小鼠的内皮功能障碍、动脉粥样硬化和心血管疾病，并延长寿命。Klotho基因编码一种单程跨膜蛋白，它以循环激素和膜结合共受体的形式存在。Klotho通过内皮调节一氧化氮的产生、血管通透性、抑制炎症和黏附分子的表达。在没有Klotho激素的情况下，在动物模型中会发生内皮功能障碍和高血压，这些都是可逆的或可以通过体内Klotho基因的传递来预防的。直到最近，还没有办法测量血液循环中的klotho水平。我们是第一个在大量人群中测量klotho水平的人。我们的初步数据支持Klotho对人类心血管疾病具有保护作用的前提。基于对Klotho的了解和我们的初步数据，我们假设循环Klotho水平低的老年人心血管事件和死亡的风险增加，Klotho水平与臂部血流介导的扩张受损有关。我们建议表征血清klotho与常见心血管疾病(心肌梗死、心绞痛、中风、充血性心力衰竭、外周动脉疾病、短暂性脑缺血)的关系。 在美国国立卫生研究院支持的、基于人群的关于冠心病和中风的纵向研究中，心血管健康研究中的心血管事件与死亡率、颈动脉内膜中层厚度、臂部血流介导的扩张、心血管事件和死亡率之间的关系。我们还将对血清klotho水平进行全基因组关联研究。该项目将确定血清klotho是否是心血管疾病的主要风险因素，并将为klotho在人类健康中的作用提供新的见解。该项目应该为Klotho作为一种潜在的心血管疾病干预新的治疗靶点提供理论基础和证据。 公共卫生相关性：该项目与公共卫生相关，因为它旨在描述最近发现的荷尔蒙klotho与美国老年人心血管疾病和心血管死亡率之间的关系。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in western countries. Despite substantial medical progress in identifying modifiable cardiovascular risk factors, a significant proportion of individuals with cardiovascular disease have no known risk factors. Klotho is a recently discovered hormone found to protect against endothelial dysfunction, atherosclerosis, and cardiovascular disease in mice, as well as to extend lifespan. The klotho gene encodes a single-pass transmembrane protein that exists as a circulating hormone and as a membrane-bound co-receptor. Klotho regulates nitric oxide production, vascular permeability, suppression of inflammation, and expression of adhesion molecules by the endothelium. In the absence of klotho hormone, endothelial dysfunction and hypertension occur in animal models, which are reversible or preventable with in vivo delivery of the klotho gene. Until recently, there was no way to measure levels of klotho in the circulation. We are the first to measure klotho levels in a large number of people. Our preliminary data support the premise that klotho is protective against cardiovascular disease in humans. Based upon knowledge of klotho and our preliminary data, we hypothesize that older people with low circulating klotho levels are at increased risk of cardiovascular events and mortality, and that klotho levels are associated with impaired brachial flow-mediated dilation. We propose to characterize the relationship of serum klotho with prevalent cardiovascular disease (myocardial infarction, angina, stroke, congestive heart failure, peripheral artery disease, transient ischemic attack), carotid intima-media thickness, brachial flow-mediated dilation, cardiovascular events and mortality in the Cardiovascular Health Study, an NIH-supported, population-based, longitudinal study of coronary heart disease and stroke in US adults. We will also conduct a genome-wide association study of serum klotho levels. This project will determine whether serum klotho is a major risk factor for cardiovascular disease and will provide novel insight into the role of klotho in human health. The project should provide the rationale and evidence for klotho as a potential novel therapeutic target for intervention in cardiovascular disease. PUBLIC HEALTH RELEVANCE: This project is relevant to public health as it aims to characterize the relationship between klotho, a recently discovered hormone, with cardiovascular disease and cardiovascular mortality in older US adults.