SORBS2 upregulation may contribute to dysfunction in LVNC via the Notch pathway.

Abstract

Background: LVNC is congenital cardiomyopathy characterized by hypertrabeculation of the left ventricle. It was reported that SORBS2, which is expressed most highly in the heart, functions in cytoskeletal organization, cell adhesion, and signaling pathways. The Notch pathway plays an important role in the development of the normal cardiovascular system, dysfunction of which can lead to cardiovascular disease. In view of the localization and function of SORBS2, we hypothesized that elevated SORBS2 might combine with the Notch pathway and be involved in the molecular mechanism of LVNC. Methods: Comparative microarray analysis was used to screen differentially expressed genes in cardiomyocytes. The high expression of SORBS2 in hESC-CMs was further confirmed by western blotting and immunohistology. Recombinant AAV9 vectors carrying SORBS2 cDNA with a cardiac-specific promoter cTNT were constructed to study the distribution and function of SORBS2 in cardiomyocytes in vivo and in vitro. Results: In our study, changes in the Notch pathway were observed in cells overexpressing SORBS2. We tested and verified the consistent trend of Tbx20, Hey2, Anf, Bmp10, and Cx40 in the Notch pathway through microarray and western blotting. In view of the localization and function of SORBS2 in the heart, we hypothesized that elevated SORBS2 might be involved in the Notch pathway and thereby participate in the molecular mechanism behind LVNC. Conclusion: Myocardial SORBS2 interacted with Cx40 and participated in the Notch pathway, resulting in myocardial fibrosis and heart function impairment. Our findings suggest that elevated myocardial SORBS2 might be involved in the molecular mechanism behind LVNC.