Abstract 5870: Blockade of the Notch Ligand Delta-like 4 (Dll4) Prevents the Cardiometabolic Syndrome
Background: Inflammation contributes to the pathogenesis of chronic metabolic disorders. Atherosclerosis, obesity, and insulin resistance represent major components of the so-called cardiometabolic syndrome, a global threat to human health. The Notch pathway, one of the fundamental signaling mechanisms that regulate development of various organs, may also participate in disease processes in the adult. We previously demonstrated in vitro that the Notch ligand Dll4 promotes inflammatory responses in macrophages such as NF-κB activation. The present study tested the hypothesis in vivo that inhibition of Dll4 prevents the development of cardiometabolic disorders.
Methods and Results: To block Dll4-mediated Notch signaling we administered anti-Dll4 antibody (Dll4-Ab) to fat-fed Ldlr−/− mice for 12 weeks. Dll4-Ab treatment retarded body weight gain (p<0.01) and reduced adipose tissue weight (p<0.05) in Ldlr−/− mice (n=10) compared with those treated with control IgG (n=9). Treated mice also showed signs of improved insulin resistance (e.g., increased GLUT4, IRS-1 and adiponectin expression in adipose tissue, and lower serum insulin levels, p<0.05, respectively). Dll4-Ab diminished adipose tissue expression and serum levels of MCP-1, a potent inducer of monocyte recruitment into the tissue, and macrophage accumulation in fat, concomitantly (p<0.05 and p<0.01, respectively). Adipose tissue of Dll4-Ab treated Ldlr−/− mice showed lower levels of NF-κB activation (e.g., increased IκBα accumulation) than control Ldlr−/− mice. In vitro studies demonstrated that in 3T3-L1 adipocytes Dll4 overexpression increased MCP-1, and that Ab blocking or RNAi silencing of Dll4 decreased this chemokine. In addition, Dll4-Ab reduced atherosclerotic plaque burden (e.g., % stenosis of brachiocephalic artery, macrophage content, calcification, MCP-1 positive area) in Ldlr−/− mice compared to control mice (n=8 each, p<0.05, respectively).
Conclusions: These results suggest that the Dll4-Notch axis promotes atherogenesis and metabolic disorders in part via MCP-1 induction and subsequent macrophage accumulation, providing novel insight into the pathogenesis and prevention of cardiometabolic syndrome.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).