Klotho and the pathogenesis of cardiovascular disease

描述（由申请人提供）：心血管疾病是西方国家发病率和死亡率的主要原因。尽管在确定可改变的心血管危险因素方面取得了实质性的医学进展，但仍有相当一部分心血管疾病患者 疾病没有已知的危险因素。Klotho是最近发现的一种激素，可以保护小鼠免受内皮功能障碍，动脉粥样硬化和心血管疾病的影响，并延长寿命。klotho基因编码一种单程跨膜蛋白，作为循环激素和膜结合辅助受体存在。Klotho调节一氧化氮的产生、血管通透性、炎症抑制和内皮细胞粘附分子的表达。在不存在klotho激素的情况下，在动物模型中发生内皮功能障碍和高血压，这是可逆的或可通过体内递送klotho基因来预防。直到最近，还没有办法测量流通中的klotho水平。我们是第一个在大量人群中测量klotho水平的公司。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率的风险增加，并且klotho水平与肱动脉血流介导的扩张受损相关。我们建议描述血清klotho与流行性心血管疾病（心肌梗死、心绞痛、中风、充血性心力衰竭、外周动脉疾病、短暂性缺血性心脏病）的关系。 心血管健康研究是一项由NIH支持的、基于人群的美国成年人冠心病和卒中纵向研究，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危险因素，并将为klotho在人类健康中的作用提供新的见解。该项目将为klotho作为心血管疾病干预的潜在新治疗靶点提供理论依据和证据。

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.