The mounting prevalence of risk factors such as aging, diabetes, and hypertension, coupled with genetic factors can perturb the cellular and molecular mechanism of the aortic valves leading to calcific aortic valve disease (CAVD) and ultimately aortic stenosis. Surgical replacement of the aortic valve remains the only and the last choice for the disease. Over 30,000 aortic valves were replaced in 2009. Patients with severe aortic stenosis who do not receive surgical valve replacement have a mortality rate of 37% at one year after symptom onset. However, replacement valves are susceptible to failure, necessitating additional surgeries. There currently is no effective medical therapy for CAVD due to the unknown etiology of the disease. Therefore, a conceptual breakthrough to develop novel targets and strategies to develop a cure for CAVD is paramount. Klotho is a recently-discovered anti- aging gene and is predominately expressed in kidneys. Klotho is a secreted protein. The level of circulating klotho declines in the aged population while the prevalence of CAVD increases in the aged population. The objective of this application is to determine, in animal models, if klotho deficiency is a causal factor of CAVD and if klotho gene delivery or klotho protein supplement could serve as an effective therapeutic strategy for CAVD. We will accomplish this objective by pursuing the following two complement specific aims. (1) Determine if klotho deficiency causes CAVD and investigate its molecular mechanism. (2) Investigate the hypothesis that in vivo klotho gene or protein delivery will attenuate or reverse CAVD in senescence-accelerated mice. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address CAVD which affects a large aged population but remains poorly explored. The results will reveal a novel etiological factor for senescence-related CAVD. The proposed research will provide important insights into therapeutic strategies for CAVD.

Public Health Relevance

Calcific aortic valve disease (CAVD) is the third leading cause of adult heart disease and is the most common form of acquired valvular disease. There is no effective medical therapy for CAVD. Completion of the project may offer a new therapeutic target for CAVD which will benefit the US population which has a high prevalence of CAVD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Evans, Frank
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
United States
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Gao, Diansa; Zuo, Zhong; Tian, Jing et al. (2016) Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity. Hypertension 68:1191-1199
Lin, Yi; Chen, Jianglei; Sun, Zhongjie (2016) Antiaging Gene Klotho Deficiency Promoted High-Fat Diet-Induced Arterial Stiffening via Inactivation of AMP-Activated Protein Kinase. Hypertension 67:564-73
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Chen, Kai; Zhou, Xiaoli; Sun, Zhongjie (2015) Haplodeficiency of Klotho Gene Causes Arterial Stiffening via Upregulation of Scleraxis Expression and Induction of Autophagy. Hypertension 66:1006-13
Lin, Yi; Sun, Zhongjie (2015) Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes. Diabetes 64:4298-311
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Lin, Yi; Sun, Zhongjie (2015) In vivo pancreatic β-cell-specific expression of antiaging gene Klotho: a novel approach for preserving β-cells in type 2 diabetes. Diabetes 64:1444-58
Sun, Zhongjie (2015) Aging, arterial stiffness, and hypertension. Hypertension 65:252-6
Zhou, Xiaoli; Chen, Kai; Lei, Han et al. (2015) Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation. J Am Soc Nephrol 26:121-32
Sun, Qisi; Zhang, Zhonge; Sun, Zhongjie (2014) The potential and challenges of using stem cells for cardiovascular repair and regeneration. Genes Dis 1:113-119

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