The IGF-1R Inhibitor NVP-AEW541 Causes Insulin-Independent and Reversible Cardiac Contractile Dysfunction

Abstract

The antitumor treatment NVP-AEW541 blocks IGF-1R. IGF-1R signaling is crucial for cardiac function, but the cardiac effects of NVP-AEW541 are ill defined. We assessed NVP-AEW541′s effects on cardiac function and insulin response in vivo and in isolated working hearts. We performed a dose–response analysis of NVP-AEW541 in male, 3-week-old rats and assessed the chronic effects of the clinically relevant dose in adult rats. We performed glucose tolerance tests and echocardiography; assessed the expression and phosphorylation of InsR/IGF-1R and Akt in vivo; and measured substrate oxidation, contractile function, and insulin response in the isolated working hearts. NVP-AEW541 caused dose-dependent growth retardation and impaired glucose tolerance in the juvenile rats. In the adults, NVP-AEW541 caused a continuously worsening depression of cardiac contractility, which recovered within 2 weeks after cessation. Cardiac Akt protein and phosphorylation were unchanged and associated with InsR upregulation. An acute application of NVP-AEW541 in the working hearts did not affect cardiac power but eliminated insulin’s effects on glucose and fatty acid oxidation. The systemic administration of NVP-AEW541 caused dose- and time-dependent impairment of glucose tolerance, growth, and cardiac function. Because cardiac insulin signaling was maintained in vivo but absent in vitro and because contractile function was not affected in vitro, a direct link between insulin resistance and contractile dysfunction appears unlikely.

Keywords

• NVP-AEW541
• small molecule
• cardiac function
• cardiac substrate oxidation
• insulin-like growth factor 1
• insulin resistance