Abstract
The present research was designed to examine the effects of disintegrin metalloproteinases 10 (ADAM10) on the doxorubicin (DOX)-induced dilated cardiomyopathy (DCM) and the mechanisms involved, with a focus on ADAM10-dependent cleavage of N-cadherin. The present study constructed recombinant lentiviral vectors expressing short hairpin RNA (shRNA) targeting the ADAM10 gene. H9C2 cells were treated with the recombinant lentivirus or GI254023 (an ADAM10 inhibitor). The expression level of N-cadherin and its C-terminal fragment1 (CTF1) was tested by western blotting and flow cytometry. The adhesion ability was analyzed using a plate adhesion model. Cardiac function and morphology were assessed in control and lentivirus-transfected rats with or without DOX treatment. The inhibition of ADAM10 activity significantly increased the expression of full-length N-cadherin on the cellular surface and reduced CTF1 generation in vivo and in vitro. The adhesion ability was also increased in ADAM10-knockdown H9C2 cells. Furthermore, DOX-induced myocardial dysfunction was ameliorated in rats transfected with ADAM10-shRNA lentivirus. These findings demonstrated that ADAM10 specifically cleaves N-cadherin in cardiomyocytes. ADAM10-induced N-cadherin cleavage results in changes in the adhesive behavior of cells. Therefore, ADAM10 may serve as a therapeutic target to reverse cardiac remodeling in DCM.
Highlights
Dilated cardiomyopathy (DCM) is a severe cardiac disorder with structural and functional myocardial abnormalities [1], which leads to high morbidity and mortality as a result of complications,including heart failure [2]
Structural cardiac remodeling involves the reorganization of the heart size and shape, which affects the progression of heart failure [16]
To investigate potential therapeutic targets that could reverse heart failure progression, novel biomarkers and mechanisms involved in cardiac remodeling must be studied
Summary
Dilated cardiomyopathy (DCM) is a severe cardiac disorder with structural and functional myocardial abnormalities [1], which leads to high morbidity and mortality as a result of complications,including heart failure [2]. The coupling of neighboring myocytes is mediated by the intercalated disc (ID) through intercellular signaling, which controls the cardiomyocyte remodeling and function [6]. It is well-known that the DCM exhibits a highly irregular structure associated with alterations of the ID components, especially the abnormal expression of proteins comprising the adherent junctions (AJs) [7]. Mice with the specific knockout of N-cadherin in cardiomyocytes exhibited disrupted assembly of ID, impaired cardiac function, and a loss in muscular tension and died within two months of transgene expression [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
