title: Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy.
abstract: 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.
  
  
  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.
authors.affiliation: Diabetes Center UCSF, San Francisco, CA 94143-0540, USA. schen@diabetes.ucsf.edu
authors.forename: Songcang
authors.initials: S
authors.lastname: Chen
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Law
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Grigsby
authors.forename: Keith
authors.initials: K
authors.lastname: Olsen
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Hong
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yerem
authors.initials: Y
authors.lastname: Yeghiazarians
authors.forename: David G
authors.initials: DG
authors.lastname: Gardner
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D018390:Gene Targeting; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics*
chemical_list: D018167:Receptors, Calcitriol