title: Amplification of lipotoxic cardiomyopathy in the VDR gene knockout mouse.
abstract: Previous studies demonstrated that the liganded vitamin D receptor (VDR) plays an important role in controlling cardiovascular homeostasis. Both the whole animal VDR gene knockout (VDR-/-) and the myocyte-specific VDR gene deletion result in changes in cardiac structure and function. Clinical states associated with cardiac steatosis (obesity and diabetes mellitus) are also associated with low circulating 25 OH vitamin D levels. We, therefore, examined the effects of VDR deficiency (VDR-/-mouse) in a murine model of cardiac steatosis that expresses the terminal enzyme involved in triglyceride synthesis, diacylglycerol acyltransferase 1 (DGAT1), selectively in the cardiac myocyte. These mice display early cardiac dysfunction and late cardiomyopathy and heart failure. In the present study, we demonstrate that mice harboring both genetic modifications (i.e., MHC-DGAT1 Tg and VDR-/-) exhibit an increase in myocyte size, heart weight/body weight ratio and natriuretic peptide gene expression, all markers of cardiac hypertrophy, that exceed that seen in either VDR-/-or the MHC-DGAT1 Tg mice alone. This was accompanied by a dramatic increase in interstitial fibrosis and increased expression of collagen 1a1 and collagen 3a1, as well as the osteopontin and matrix metalloproteinase 2, genes. At a functional level, this resulted in a 37% reduction in ejection fraction and 55% reduction in fractional shortening in the DGAT1; VDR-/-mice relative to the controls. Collectively, these data demonstrate that deficiency in the vitamin D signaling system enhances the pathological phenotype in this experimental cardiomyopathy and suggest an important role for vitamin D in modulating disease severity in common cardiovascular disorders.
authors.affiliation: Diabetes Center, 1109 HSW, University of California San Francisco, San Francisco, CA 94143-0540, United States. Electronic address: dglenn@diabetes.ucsf.edu.
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Glenn
authors.affiliation: Diabetes Center, 1109 HSW, University of California San Francisco, San Francisco, CA 94143-0540, United States.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Cardema
authors.affiliation: Diabetes Center, 1109 HSW, University of California San Francisco, San Francisco, CA 94143-0540, United States.
authors.forename: David G
authors.initials: DG
authors.lastname: Gardner
mesh_terms: D000818:Animals; D001835:Body Weight; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D004546:Elapid Venoms / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics*; D013318:Stroke Volume
chemical_list: C542600:CD-NP natriuretic peptide; D024042:Collagen Type I; D024061:Collagen Type III; D004546:Elapid Venoms; D018167:Receptors, Calcitriol; C506896:Spp1 protein, mouse; D053495:Osteopontin; D020098:Natriuretic Peptide, C-Type; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: Cardiac fibrosis; Cardiac steatosis; Diacylglycerol acyltransferase 1 (DGAT1); Vitamin D receptor (VDR)