Molecular Cardiology Cardiomyocyte-Specific Deletion of the Vitamin D Receptor Gene Results in Cardiac Hypertrophy

Background—A variety of studies carried out using either human subjects or laboratory animals suggest that vitamin D and its analogues possess important beneficial activity in the cardiovascular system. Using Cre-Lox technology we have selectively deleted the vitamin D receptor (VDR) gene in the cardiac myocyte in an effort to better understand the role of vitamin D in regulating myocyte structure and function. Methods and Results—Targeted deletion of the exon 4 coding sequence in the VDR gene resulted in an increase in myocyte size and left ventricular weight/body weight versus controls both at baseline and following a 7-day infusion of isoproterenol. There was no increase in interstitial fibrosis. These knockout mice demonstrated a reduction in end-diastolic and end-systolic volume by echocardiography, activation of the fetal gene program (ie, increased atrial natriuretic peptide and alpha skeletal actin gene expression), and increased expression of modulatory calcineurin inhibitory protein 1 (MCIP1), a direct downstream target of calcineurin/nuclear factor of activated T cell signaling. Treatment of neonatal cardiomyocytes with 1,25-dihydroxyvitamin D partially reduced isoproterenol-induced MCIP1 mRNA and protein levels and MCIP1 gene promoter activity. Conclusions—Collectively, these studies demonstrate that the vitamin D-VDR signaling system possesses direct, antihypertrophic activity in the heart. This appears to involve, at least in part, suppression of the prohypertrophic calcineurin/NFAT/MCIP1 pathway. These studies identify a potential mechanism to account for the reported beneficial effects of vitamin D in the cardiovascular system. V itamin D is ingested in the diet or generated de novo through scission of cholesterol precursors in the skin by ultraviolet light. 1 Once formed, vitamin D is activated through 2 sequential hydroxylation reactions. The first of these, a 25-hydroxylation, takes place largely in the liver to produce 25-hydroxyvitamin D. This molecule circulates bound to a plasma protein and is the form that is measured to assess the adequacy of vitamin D stores in the organism. The second hydroxylation, a 1␣-hydroxylation, takes place in a variety of tissues, including the kidney, to generate 1,25-dihydroxyvitamin D [1,25(OH) 2 D], the most polar and biologically active of the vitamin D metabolites. 1,25(OH) 2 D functions as a ligand for the nuclear vitamin D receptor (VDR) which, when paired with its heterodimeric retinoid X receptor partner, binds to sequence-specific recognition elements on DNA and stimulates or represses transcription of contiguous genes. 2 The prevalence of vitamin D deficiency and insufficiency (ie, plasma levels of 25-hydroxyvitamin D Ͻ20 and Ͻ30 ng/mL, respectively) is …