The role of vitamin D(3) in regulating myocardial development.

Abstract

Since the discovery of the receptor for 1,25-dihydroxyvitamin D$\sb3$ (1,25(OH)$\sb2$D$\sb3$) in left ventricular tissue and in cultured myocytes, several studies have been done to characterize how the vitamin D endocrine system affects the cardiovascular system. Much of the current knowledge regarding the effects of vitamin D$\sb3$ on the cardiovascular system was obtained using the vitamin D$\sb3$-deficient rat heart model. Previous studies performed with vitamin D$\sb3$-deficient rats demonstrated that vitamin D$\sb3$ deficiency increased contractility and induced myocardial hypertrophy. The current project was designed to determine the mechanisms by which vitamin D deficiency altered myocardial function and morphology. It was determined that changes in contractility produced by vitamin D$\sb3$ deficiency were correlated with an increase in V$\sb1$ myosin isozyme expression. Furthermore, vitamin D$\sb3$ deficiency altered myocardial morphology by inducing myocyte hyperplasia and increasing myocardial c-myc levels. These studies therefore suggested that vitamin D$\sb3$ deficiency may be regulating both myocyte growth and differentiation. To test this hypothesis, the effects of 1,25(OH)$\sb2$D$\sb3$ were tested directly on primary cultures of ventricular myocytes. It was shown that 1,25(OH)$\sb2$D$\sb3$ inhibited myocyte proliferation and induced myocyte hypertrophy. Additionally, 1,25(OH)$\sb2$D$\sb3$ inhibited myocyte maturation by blocking the expression of the mature forms of several myocyte specific proteins, including creatine kinase and myosin. Interestingly, the effects of 1,25(OH)$\sb2$D$\sb3$ on myocyte growth and maturation are mimicked by phorbol esters. Furthermore, staurosporine, an inhibitor of protein kinase C (PKC), blocked the effects of 1,25(OH)$\sb2$D$\sb3$ to induce myocyte hypertrophy. This suggests that the effects of 1,25(OH)$\sb2$D$\sb3$ in myocytes are mediated by PKC. These studies identify a novel role for 1,25(OH)$\sb2$D$\sb3$ in the regulation of myocardial development and suggest that 1,25(OH)$\sb2$D$\sb3$ may be acting through a protein kinase dependent mechanism to regulate cardiac myocyte growth and differentiation.