Inhibiting Insulin-Mediated β2AR Activation Prevents Diabetes-Associated Cardiac Dysfunction

• Published in: Circulation (New York, N.Y.) Vol. 135; no. 1; pp. 73 - 88
• Main Authors: Wang, Qingtong, Liu, Yongming, Fu, Qin, Xu, Bing, Zhang, Yuan, Kim, Sungjin, Tan, Ruensern, Barbagallo, Federica, West, Toni, Anderson, Ethan, Wei, Wei, Abel, E Dale, Xiang, Yang K
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 18-11-2016
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.116.022281

BACKGROUND—Type-2 diabetes and obesity independently increases the risk of heart failure via incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in hearts of subjects with type-2 diabetes and obesity.
METHODS—High fat diet feeding was used to induce obesity and diabetes in wild type mice or mice lacking β2-adrenergic receptor (β2AR) or β -arrestin2. Wild type mice fed with high fat diet were treated with β -blocker carvedilol or G-protein receptor kinase 2 (GRK2) inhibitor. We examined the signaling and cardiac contractile function.
RESULTS—High fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced PKA phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with diabetes. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and (GRK2) and β-arrestin2-dependent transactivation of a β2AR-ERK signaling cascade. Thus pharmacological inhibition of β2AR or GRK2, or genetic deletion of β2AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of ERK and PDE4D induction, to prevent diabetes-related contractile dysfunction.
CONCLUSIONS—These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β2AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type-2 diabetes.