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.
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.
Authors: Nalini M Rajamannan; Frank J Evans; Elena Aikawa; K Jane Grande-Allen; Linda L Demer; Donald D Heistad; Craig A Simmons; Kristyn S Masters; Patrick Mathieu; Kevin D O'Brien; Frederick J Schoen; Dwight A Towler; Ajit P Yoganathan; Catherine M Otto Journal: Circulation Date: 2011-10-18 Impact factor: 29.690
Authors: Meritxell Nus; Donal MacGrogan; Beatriz Martínez-Poveda; Yolanda Benito; Jesús C Casanova; Francisco Fernández-Avilés; Javier Bermejo; José Luis de la Pompa Journal: Arterioscler Thromb Vasc Biol Date: 2011-04-14 Impact factor: 8.311
Authors: Gaurav Luther; Eric R Wagner; Gaohui Zhu; Quan Kang; Qing Luo; Joseph Lamplot; Yang Bi; Xiaoji Luo; Jinyong Luo; Chad Teven; Qiong Shi; Stephanie H Kim; Jian-Li Gao; Enyi Huang; Ke Yang; Richard Rames; Xing Liu; Mi Li; Ning Hu; Hong Liu; Yuxi Su; Liang Chen; Bai-Cheng He; Guo-Wei Zuo; Zhong-Liang Deng; Russell R Reid; Hue H Luu; Rex C Haydon; Tong-Chuan He Journal: Curr Gene Ther Date: 2011-06 Impact factor: 4.391
Authors: Damien N Barnette; Alexia Hulin; A S Ishtiaq Ahmed; Alain C Colige; Mohamad Azhar; Joy Lincoln Journal: J Mol Cell Cardiol Date: 2013-10-21 Impact factor: 5.000