Increased dietary intake of vitamin A promotes aortic valve calcification in vivo. Arterioscler Thromb Vasc Biol 2013 Feb;33(2):285-93
Date
12/04/2012Pubmed ID
23202364Pubmed Central ID
PMC3557503DOI
10.1161/ATVBAHA.112.300388Scopus ID
2-s2.0-84872978085 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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.
METHODS AND 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.
Author List
Huk DJ, Hammond HL, Kegechika H, Lincoln JAuthor
Joy Lincoln PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAortic Valve
Calcinosis
Cell Line
Chick Embryo
Collagen Type II
Dietary Supplements
Disease Models, Animal
Diterpenes
Gene Expression Profiling
Gene Expression Regulation
Heart Valve Diseases
Hypervitaminosis A
Mice
Mice, Inbred C57BL
Oligonucleotide Array Sequence Analysis
Osteogenesis
Osteopontin
RNA Interference
Receptors, Retinoic Acid
Retinoid X Receptors
SOX9 Transcription Factor
Signal Transduction
Time Factors
Tissue Culture Techniques
Transfection
Tretinoin
Vitamin A
Vitamins