Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice.
1alpha,25-Dihydroxyvitamin D(3) [1,25D] deficiency and vitamin D receptor [VDR] genotypes are risk factors for several diseases and disorders including heart diseases. Extracellular matrix (ECM) remodeling mediated by matrix metalloproteinases [MMPs] contributes to progressive left ventricular remodeling, dilation, and heart failure. In the present study, we used high-density oligonucleotide microarray to examine gene expression profile in wild type [WT] and vitamin D receptor knockout mice (VDR KO) which was further validated by RT-PCR. Microarray analysis revealed tissue inhibitors of metalloproteinases [TIMP-1 and TIMP-3] were significantly under expressed in VDR KO mice as compared to WT mice which was further validated by RT-PCR. Zymography and RT-PCR showed that MMP-2 and MMP-9 were up regulated in VDR KO mice. In addition, cross-sectional diameter and longitudinal width of the VDR KO heart myofibrils showed highly significant cellular hypertrophy. Trichrome staining showed marked increase in fibrotic lesions in the VDR KO mice. Heart weight to body weight ratio showed approximately 41% increase in VDR KO mice when compared to WT mice. This data supports a role for 1,25D in heart ECM metabolism and suggests that MMPs and TIMPs expression may be modulated by vitamin D.
Rahman
Ayesha
A
Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632, USA.
Hershey
Stephen
S
Ahmed
Salahuddin
S
Nibbelink
Karl
K
Simpson
Robert U
RU
D000818:Animals; D001835:Body Weight; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D018167:Receptors, Calcitriol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9