Abstract 9095: Induction of Modulatory Calcineurin Inhibitory Protein 1 as a Potential Mechanism Leading to Cardiac Hypertrophy in the Cardiomyocyte-Specific Vitamin D Receptor Gene-Deleted Mouse
A growing body of epidemiological, clinical, and whole animal studies has shown that vitamin D deficiency is linked with increased risk of cardiovascular disease, including cardiac hypertrophy. Although global nuclear vitamins D receptor (VDR)-null mice display cardiac hypertrophy, the mice also demonstrate hypertension and secondary hyperparathyroidism, both of which are associated with cardiac hypertrophy. Therefore, it remains unknown as to whether the liganded VDR interacts directly with the cardiac myocyte to control hypertrophy. In an effort to address this issue, we have generated a mouse with selective deletion of the VDR gene in cardiomyocytes. Targeted deletion of exon 4 in the VDR gene resulted in an increase in myocyte size and left ventricular weight/body weight versus controls both at baseline and following chronic infusion of isoproterenol (ISO). 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 (i.e. increased ANP and alpha skeletal actin gene expression) and increased expression of the modulatory calcineurin inhibitory protein 1 (MCIP 1), a direct downstream target of calcineurin/NFAT signaling that plays an important role in cardiac hypertrophy. ISO treatment of neonatal rat cardiomyocytes resulted in a significant increase in MCIP 1 mRNA and protein levels and MCIP 1 gene promoter activity. Treatment with 1,25 dihydroxyvitamin D (VD3), a potent VDR ligand, resulted in partial suppression of the ISO-dependent increases in MCIP 1 expression and promoter activity. Renin gene expression was extremely low at baseline in the adult murine left ventricle and did not increase significantly in the left ventricles of cardiomyocyte-specific VDR knockout mice. Collectively, these studies provide the first demonstration that the VD3-VDR signaling system possesses direct, anti-hypertrophic activity in the heart. This activity may be linked to suppression of the pro-hypertrophic calcineurin/NFAT/MCIP 1 pathway. These studies identify a potential mechanism to account for the reported beneficial effects of VD3 in cardiac disorders associated with myocyte hypertrophy.
- © 2011 by American Heart Association, Inc.