GDF 11 is essential for maintaining cardiac function under pressure overload




Description

Jingyun Zhu, Yun Zhao, Ning Zhang, JianAn Wang, Hong Yu

Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

Objective: Growth differentiation factor 11 (GDF11) is a member of transforming growth factor ꞵ superfamily. The physiological and pathological functions of GDF11 in cardiomyocytes and heart remain unclear. Here we sought to elucidate the cardiomyocyte-specific roles and mechanism of GDF11 in pathological cardiac hypertrophy.

Methods and Results: GDF11 expression was increased in human hearts with dilated cardiomyopathy (DCM) and myocardial infarcted (MI), which was confirmed in mouse models of hearts after transverse aortic constriction (TAC) and MI. GDF11 in heart was mainly derived from cardiomyocytes. Cardiac specific GDF11 conditional knockout (CKO) and control Cre mice were subjected to TAC-mediated pressure overload or MI. Deficiency of GDF11 accelerated cardiac dysfunction and left ventricular dilatation after TAC or MI. More fibrosis and fewer vasculatures were detected in the hearts of CKO mice after TAC or MI as compared with controls. GDF11 overexpression with cardiac injection of AAV9-GDF11 during TAC procedure rescued the detrimental cardiac function of CKO mice. In vitro culture, GDF11 overexpression in CMs resulted in more VEGF secretion. The conditioned medium from GDF11-overexpressed CMs stimulated significantly more tube formation of endothelial cells, which could be blocked by VEGF neutralizing antibody. GDF11 overexpression promoted the phosphorylation of Smad2/3 and Akt/protein kinase B (AKT) in CMs. Inhibition of TGF-ꞵ/Smad signal pathway by TGF-ꞵ receptor inhibitor (SB431542) blunted the GDF11-induced CM’s paracrine effect.

Conclusions: GDF11 functions as an injury-induced cardiokine that stimulates paracrine effect of CMs to protect myocardium from injury.

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