Abstract 122: Hyperinsulinmia Promotes Cardiac Dysfunction via Upregulation of Phosphodiesterase in Heart

Abstract

Accumulating evidence suggests that hyperinsulinemia contributes to heart dysfunction. Here we show that insulin signaling is responsible for high fat diet (HFD) feeding-induced expression of phosphodiesterase 4D (PDE4D) in the myocardium of mice. The increased expression of PDE4D, in concert with reduced phosphorylation of phospholamban (PLB), promotes systolic and diastolic heart dysfunction. We revealed that insulin-mediated induction of PDE4D was dependent on β2AR-mediaed β-arrestin2-ERK pathway, which is transactivated in a GRK2-dependent fashion. Deletion of β2AR gene significantly attenuated insulin-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, as well as the upregulation of PDE4D expression, which prevented the heart dysfunction. β-arrestin2 KO mice did not display increased PDE4D expression and did not develop systolic or diastolic dysfunction following HFD. In brief, these data indicate that chronic hyperinsulinimia leads to heart dysfunction by increasing PDE4D expression via β2AR-GRK2-β-arrestin2 -ERK pathway, which suggests that β2AR signaling could be an attractive therapeutic target for preserving or improving cardiac function in subjects with insulin resistance.