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Krox20 Regulates Endothelial Nitric Oxide Signaling in Aortic Valve Development and Disease

Abstract : Among the aortic valve diseases, the bicuspid aortic valve (BAV) occurs when the aortic valve has two leaflets (cusps), rather than three, and represents the most common form of congenital cardiac malformation, affecting 1-2% of the population. Despite recent advances, the etiology of BAV is poorly understood. We have recently shown that Krox20 is expressed in endothelial and cardiac neural crest derivatives that normally contribute to aortic valve development and that lack of Krox20 in these cells leads to aortic valve defects including partially penetrant BAV formation. Dysregulated expression of endothelial nitric oxide synthase (Nos3) is associated with BAV. To investigate the relationship between Krox20 and Nos3 during aortic valve development, we performed inter-genetic cross. While single heterozygous mice had normal valve formation, the compound Krox20+/−;Nos3+/− mice had BAV malformations displaying an in vivo genetic interaction between these genes for normal valve morphogenesis. Moreover, in vivo and in vitro experiments demonstrate that Krox20 directly binds to Nos3 proximal promoter to activate its expression. Our data suggests that Krox20 is a regulator of nitric oxide in endothelial-derived cells in the development of the aortic valve and concludes on the interaction of Krox20 and Nos3 in BAV formation.
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Submitted on : Wednesday, January 15, 2020 - 4:31:28 PM
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Gaelle Odelin, Emilie Faure, Corinne Maurel-Zaffran, Stéphane Zaffran. Krox20 Regulates Endothelial Nitric Oxide Signaling in Aortic Valve Development and Disease. Journal of Cardiovascular Development and Disease, MDPI, 2019, 6 (4), pp.39. ⟨10.3390/jcdd6040039⟩. ⟨hal-02441235⟩



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