ReviewAmplification of lipotoxic cardiomyopathy in the VDR gene knockout mouse

- Deletion of the vitamin D receptor results in increased hypertrophy and a marked increase in cardiac fibrosis in the setting of cardiac steatosis.
- The increase in fibrosis may result from an increase in TGFβ expression.

Previous studies demonstrated that the liganded vitamin D receptor (VDR) plays an important role in controlling cardiovascular homeostasis. Both the whole animal VDR gene knockout (VDR−/−) and the myocyte-specific VDR gene deletion result in changes in cardiac structure and function. Clinical states associated with cardiac steatosis (obesity and diabetes mellitus) are also associated with low circulating 25 OH vitamin D levels. We, therefore, examined the effects of VDR deficiency (VDR−/− mouse) in a murine model of cardiac steatosis that expresses the terminal enzyme involved in triglyceride synthesis, diacylglycerol acyltransferase 1 (DGAT1), selectively in the cardiac myocyte. These mice display early cardiac dysfunction and late cardiomyopathy and heart failure. In the present study, we demonstrate that mice harboring both genetic modifications (i.e., MHC-DGAT1 Tg and VDR−/−) exhibit an increase in myocyte size, heart weight/body weight ratio and natriuretic peptide gene expression, all markers of cardiac hypertrophy, that exceed that seen in either VDR−/− or the MHC-DGAT1 Tg mice alone. This was accompanied by a dramatic increase in interstitial fibrosis and increased expression of collagen 1a1 and collagen 3a1, as well as the osteopontin and matrix metalloproteinase 2, genes. At a functional level, this resulted in a 37% reduction in ejection fraction and 55% reduction in fractional shortening in the DGAT1; VDR−/− mice relative to the controls. Collectively, these data demonstrate that deficiency in the vitamin D signaling system enhances the pathological phenotype in this experimental cardiomyopathy and suggest an important role for vitamin D in modulating disease severity in common cardiovascular disorders.