Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe−/− mice

Abstract

BackroundGlucagon-like peptide-1 (GLP-1) based therapies are new treatment options for patients with type 2 diabetes. Recent reports suggest vasoprotective actions of GLP-1. Similar beneficial effects might be reached by GLP-1(9-37) and the c-terminal GLP-1 split product (28-37) although both peptides do not activate the GLP-1 receptor. We therefore investigated the actions of GLP-1(7-37), GLP-1(9-37) as well as GLP-1(28-37) on vascular lesion formation in a mouse model of atherosclerosis. Methods and resultsGLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) and LacZ (control) were overexpressed for a period of 12 weeks in apoe−/− mice on high-fat diet (n = 10/group) using an adeno-associated viral vector system. Neither of the constructs changed overall lesion size. However, GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) significantly reduced plaque macrophage infiltration (GLP-1(7-37): 40.6%, GLP-1(9-37): 47.0%, GLP-1(28-37): 40.1% decrease, p < 0.05) and plaque MMP-9 expression (GLP-1(7-37): 41.6%, GLP-1(9-37): 50.2%, GLP-1(28-37): 44.0% decrease, p < 0.05) compared to LacZ in the aortic arch. Moreover, all GLP-1 constructs increased plaque collagen content (GLP-1(7-37): 49.3%, GLP-1(9-37): 86.0%, GLP-1(28-37): 81.9% increase, p < 0.05) and increased fibrous cap thickness (GLP-1(7-37): 188.0%, GLP-1(9-37): 179.9% GLP-1(28-37): 111.0% increase, p < 0.05).These effects of GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) on plaque macrophage infiltration, MMP-9 expression and plaque collagen content were confirmed in the aortic root. ConclusionGLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) reduce plaque inflammation and increase phenotypic characteristics of plaque stability in a murine model of atherosclerosis.Future studies are needed to determine whether these effects translate into improved plaque stability and less cardiovascular events in high-risk patients with type 2 diabetes.