Heart is now recognized as a target organ for 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3). Receptors (VDRs) for this hormone exist in rodent and human cardiomyocytes and microarray analysis of heart revealed the expression of the VDR. We now know that decreased production of 1,25(OH)2D3 and decreased vitamin D intake are problems associated with aging and are relevant to several diseases, including heart disease. Our studies have shown that vitamin D deficiency or decreased production of 1,25(OH)2 D3 causes or exacerbates pathological conditions of the heart. The hormone affects rat heart structure, function, differentiation and morphology. In recent clinical studies it was shown that decreased levels of vitamin D metabolites in humans correlates with the incidence of heart failure. Collagen over expression and decreased collagenase (MMPs) levels are associated with the failing heart. Heart failure is a common event in the elderly and U.S. costs for its treatment exceed 5 billion $ annually. Thus, the biology of heart matrix formation, collagen expression and turnover are subjects of great importance. The observation that vitamin D depleted rat hearts have increased collagen content, altered extracellular matrix (fibrosis) and organ hypertrophy that resemble changes seen in the aging and failing heart is central to the interest and to the focus of this proposal. I hypothesize that 1,25(OH)2D3 plays a role in regulating myocardial collagen expression and is in part responsible for the changes in extracelluar matrix and function seen in the failing and senescent heart.
My specific aims to address this hypothesis are: 1) to establish the collagen isotypes regulated by vitamin D deficiency in the rat; 2) to examine the effects of 1,25(OH)2D3 and the newer noncalcemic analogs of 1,25(OH)2D3 on collagen and MMPs in heart using the spontaneouly hypertensive rat (SHHF) model for the failing heart and 3) to examine the role of PKC in the actions of 1,25(OH)2D3 to regulate collagen and MMP expression and levels in myocytes and fibroblasts from control and SHHF rat. This study will provide novel information about the importance of vitamin D and the potential of 1,25(OH)2D3 related therapeutics to regulate heart collagen formation in a model for the failing heart. Moreover, it will determine if decreased vitamin D metabolite levels correlate with changes in heart collagen and MMP in an established model of heart failure.
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