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.

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 Japanese-American men.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZHL1-CSR-P (F2))
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Wagner, Elizabeth
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Johns Hopkins University
Schools of Medicine
United States
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Drew, David A; Katz, Ronit; Kritchevsky, Stephen et al. (2017) Association between Soluble Klotho and Change in Kidney Function: The Health Aging and Body Composition Study. J Am Soc Nephrol 28:1859-1866
Semba, Richard D; Ferrucci, Luigi; Sun, Kai et al. (2016) Low Plasma Klotho Concentrations and Decline of Knee Strength in Older Adults. J Gerontol A Biol Sci Med Sci 71:103-8
Shardell, Michelle; Semba, Richard D; Rosano, Caterina et al. (2016) Plasma Klotho and Cognitive Decline in Older Adults: Findings From the InCHIANTI Study. J Gerontol A Biol Sci Med Sci 71:677-82
Semba, Richard D; Enghild, Jan J (2014) Proteomics and the eye. Proteomics Clin Appl 8:127-9
Semba, Richard D; Enghild, Jan J; Venkatraman, Vidya et al. (2013) The Human Eye Proteome Project: perspectives on an emerging proteome. Proteomics 13:2500-11