title: Increased dietary intake of vitamin A promotes aortic valve calcification in vivo.
abstract: OBJECTIVE
  Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro.
  
  
  RESULTS
  Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors.
  
  
  CONCLUSIONS
  Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.
authors.affiliation: Center for Cardiovascular and Pulmonary Research, Columbus, OH, USA.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Huk
authors.forename: Harriet L
authors.initials: HL
authors.lastname: Hammond
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kegechika
authors.forename: Joy
authors.initials: J
authors.lastname: Lincoln
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology; D002114:Calcinosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002642:Chick Embryo; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004224:Diterpenes; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006349:Heart Valve Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006986:Hypervitaminosis A / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010012:Osteogenesis / Q000235:genetics; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D000084562:Retinyl Esters; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000378:metabolism; D014815:Vitamins / Q000378:metabolism
chemical_list: D024043:Collagen Type II; D004224:Diterpenes; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D000084562:Retinyl Esters; D055758:SOX9 Transcription Factor; D014815:Vitamins; D053495:Osteopontin; D014801:Vitamin A; C014794:retinol palmitate; D014212:Tretinoin