Robert U. Simpson

A number of investigators have observed insufficient 25-hydroxyvitamin D status in patients with congestive heart failure, suggesting a role for vitamin D insufficiency in the pathogenesis of this disorder. We have observed cardiac hypertrophy and collagen accumulation in rats deficient in vitamin D and in the hearts of vitamin D-receptor knockout mice. Our studies indicate that absence of vitamin D-mediated signal transduction and genomic activation results in cardiomyocytes overstimulation including increased contractility. These events ultimately lead to cardiomyocyte hypertrophy. In this report, we used spontaneously hypertensive heart failure rats cp/+ (hemyzygous for the corpulent gene, a mutant isoform of the leptin receptor) fed a normal and a high-salt diet to assess the potential for activated vitamin D (1,25 dihydroxyvitamin D₃) to prevent cardiac hypertrophy and increases in cardiac output. After 13 weeks, as compared with untreated rats, we observed that 1,25 dihydroxyvitamin D₃ treatment in rats fed a high-salt diet resulted in lower heart weight, myocardial collagen levels, left ventricular diameter, and cardiac output despite higher serum leptin levels. These studies suggest that 1,25(OH)₂D₃ treatment may prevent the development of cardiac hypertrophy, an important contributing factor in the progression of congestive heart failure.

We have previously shown that the active form of vitamin D, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], has both genomic and rapid nongenomic effects in heart cells; however, the subcellular localization of the vitamin D receptor (VDR) in heart has not been studied. Here we show that in adult rat cardiac myocytes the VDR is primarily localized to the t-tubule. Using immunofluorescence and Western blot analysis, we show that the VDR is closely associated with known t-tubule proteins. Radioligand binding assays using 3H-labeled 1,25(OH)2D3 demonstrate that a t-tubule membrane fraction isolated from homogenized rat ventricles contains a 1,25(OH)2D3-binding activity similar to the classic VDR. For the first time, we show that cardiac myocytes isolated from VDR knockout mice show accelerated rates of contraction and relaxation as compared with wild type and that 1,25(OH)2D3 directly affects contractility in the wild-type but not the knockout cardiac myocyte. Moreover, we observed that acute (5 min) exposure to 1,25(OH)2D3 altered the rate of relaxation. A receptor localized to t-tubules in the heart is ideally positioned to exert an immediate effect on signal transduction mediators and ion channels. This novel discovery is fundamentally important in understanding 1,25(OH)2D3 signal transduction in heart cells and provides further evidence that the VDR plays a role in heart structure and function.