Deficiency of Sox7 leads to congenital aortic stenosis via abnormal valve remodeling.

Abnormal valve development is the most common congenital heart malformation. The transcription factor Sox7 plays a critical role in the development of vascular and cardiac septation. However, it remains unclear whether Sox7 is required for heart valve development. In the present study, Sox7 was strongly expressed in the endocardial and mesenchymal cells of the developing aortic valve in mice and humans, and that endocardial cell specific deletion of Sox7 (Nfatc1 Cre;Sox7) in mice leads to congenital aortic stenosis basing on our echocardiography data and multiple staining results. Mechanistically, Sox7 influences extracellular matrix (ECM) remodeling of the valve through regulating MMP9. Meanwhile, Sox7 also affects other valvular remodeling processes, including apoptosis and proliferation of valvular cells in Sox7 deficiency mice. Similarly, in valvular interstitial cells (VICs), Sox7 overexpression increased the protein levels of cleaved caspase3 and TUNEL-positive VICs, while Ki67-positive VICs decreased. The reverse trend was observed in VICs with Sox7 deficiency. Significant enhancement of Rbm25 transcriptional levels was observed in the Sox7 overexpression group, and the mRNA and protein levels of calcification markers such as Osterix, Osteopontin and Runx2 were reduced. The reverse trend was observed in VICs with Sox7 deficiency. Von Kossa staining and Alizarin Red staining also demonstrated that sever calcification in Nfatc1 Cre;Sox7 mice. Moreover, we detected the Sox7 protein expression in human fetal aortic valves in patients with aortic stenosis, in which Sox7 positive mesenchymal cells were decreased. Taken together, these findings identify Sox7 as a potential pathogenic gene responsible for congenital aortic stenosis in human. Our study provides novel strategies for the diagnosis and treatment of congenital valvular malformation.