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

• Published in: Circulation (New York, N.Y.) Vol. 124; no. 17; pp. 1838 - 1847
• Main Authors: Chen, Songcang, Law, Christopher S., Grigsby, Christopher L., Olsen, Keith, Hong, Ting-Ting, Zhang, Yan, Yeghiazarians, Yerem, Gardner, David G.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 25.10.2011
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiomegaly - etiology; Cardiomegaly - genetics; Cardiomegaly - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Gene Deletion; Gene Targeting; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Medical sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Receptors, Calcitriol - deficiency; Receptors, Calcitriol - genetics; Agonist; Isoprenaline; Bronchodilator; β2-Adrenergic receptor; β-Adrenergic receptor agonist; Cardiovascular disease; isoproterenol; β-Adrenergic receptor; gene deletion; Vitamin D; Deletion; vitamin D receptor; cardiac hypertrophy
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.111.032680

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. 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. 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.