Klotho and cardiovascular disease in the Honolulu Heart Program

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这样一个前提，即Klotho对人类心血管疾病具有保护作用，循环中的Klotho水平显著增加C指数，超出传统的心血管风险 与常见心血管疾病有关的因素。基于对Klotho的了解和我们的初步数据，我们假设循环Klotho水平低的男性心血管事件和死亡的风险增加。我们建议在火奴鲁鲁心脏计划中将血清Klotho作为冠心病、中风以及心血管和全原因死亡率的预测因子的特征，该计划是一项由NIH支持的关于日裔美国男性冠心病和中风的前瞻性研究。该项目将确定血清Klotho是否是心血管疾病的主要独立风险因素，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。

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 and that circulating klotho levels significantly increase the C-index beyond traditional cardiovascular risk factors in relation to prevalent cardiovascular disease. Based upon knowledge of klotho and our preliminary data, we hypothesize that men with low circulating klotho levels are at increased risk of cardiovascular events and mortality. We propose to characterize the relationship of serum klotho as a predictor of incident coronary heart disease, stroke, and cardiovascular and all-cause mortality in the Honolulu Heart Program, an NIH-supported, prospective study of coronary heart disease and stroke in Japanese-American men. This project will determine whether serum klotho is a major independent 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.