tretinoin and Heart-Valve-Diseases

Retinoic acid (RA) is a ligand for nuclear receptors that modulate gene transcription and cell differentiation. Whether RA controls ectopic calcification in humans is unknown. We tested the hypothesis that RA regulates osteogenic differentiation of human arterial smooth muscle cells and aortic valvular interstitial cells that participate in atherosclerosis and heart valve disease, respectively. Approach and Results: Human cardiovascular tissue contains immunoreactive RAR (RA receptor)-a retinoid-activated nuclear receptor directing multiple transcriptional programs. RA stimulation suppressed primary human cardiovascular cell calcification while treatment with the RAR inhibitor AGN 193109 or. These results establish retinoid regulation of human cardiovascular calcification, provide new insight into mechanisms involved in these responses, and suggest selective retinoid modulators, like acyclic retinoids may allow for treating cardiovascular calcification without the adverse effects associated with cyclic retinoids.

Topics: Alkaline Phosphatase; Aortic Valve; Apolipoprotein C-III; Calcium-Binding Proteins; Carotid Arteries; Carrier Proteins; Cells, Cultured; Cholesterol 7-alpha-Hydroxylase; Coronary Vessels; Extracellular Matrix Proteins; Heart Valve Diseases; Humans; Isotretinoin; Matrix Gla Protein; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteogenesis; Receptors, Retinoic Acid; Retinoids; Signal Transduction; Tretinoin; Vascular Calcification

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.. 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.. 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.

Topics: Animals; Aortic 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; Receptors, Retinoic Acid; Retinoid X Receptors; Retinyl Esters; RNA Interference; Signal Transduction; SOX9 Transcription Factor; Time Factors; Tissue Culture Techniques; Transfection; Tretinoin; Vitamin A; Vitamins

Calcification of heart valve structures is the most common form of valvular disease and is characterized by the appearance of bone-like phenotypes within affected structures. Despite the clinical significance, the underlying etiology of disease onset and progression is largely unknown and valve replacement remains the most effective treatment. The SRY-related transcription factor Sox9 is expressed in developing and mature heart valves, and its function is required for expression of cartilage-associated proteins, similar to its role in chondrogenesis. In addition to cartilage-associated defects, mice with reduced sox9 function develop skeletal bone prematurely; however, the ability of sox9 deficiency to promote ectopic osteogenic phenotypes in heart valves has not been examined.. This study aims to determine the role of Sox9 in maintaining connective tissue homeostasis in mature heart valves using in vivo and in vitro approaches.. Using histological and molecular analyses, we report that, from 3 months of age, Sox9(fl/+);Col2a1-cre mice develop calcific lesions in heart valve leaflets associated with increased expression of bone-related genes and activation of inflammation and matrix remodeling processes. Consistently, ectopic calcification is also observed following direct knockdown of Sox9 in heart valves in vitro. Furthermore, we show that retinoic acid treatment in mature heart valves is sufficient to promote calcific processes in vitro, which can be attenuated by Sox9 overexpression.. This study provides insight into the molecular mechanisms of heart valve calcification and identifies reduced Sox9 function as a potential genetic basis for calcific valvular disease.

Topics: Age Factors; Aging; Animals; Animals, Newborn; Calcinosis; Calcium; Chick Embryo; Collagen Type II; Disease Models, Animal; Down-Regulation; Extracellular Matrix; Female; Gene Knockdown Techniques; Genotype; Heart Valve Diseases; Inflammation; Integrases; Male; Mice; Mice, Transgenic; Mitral Valve; Osteogenesis; Phenotype; SOX9 Transcription Factor; Tissue Culture Techniques; Transfection; Tretinoin; Tricuspid Valve