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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111271-03
Application #
8675929
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Hasan, Ahmed a K
Project Start
2012-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$356,691
Indirect Cost
$120,628
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Semba, Richard D; Moghekar, Abhay R; Hu, Jason et al. (2014) Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease. Neurosci Lett 558:37-40