Abstract 310: GLP-1 Cleavage Product (9-36)-NH2 Exerts Pro-survival Effects on Smooth Muscle Cells in Advanced Inflammatory Hemodynamic Conditions

Glucagon-like peptide-1(GLP-1), an incretin hormone, has been shown to have atheroprotective effects on the cardiovascular system in animal models of atherosclerosis and diabetes, and in several clinical trials. These beneficial effects are presumed to occur through active GLP-1 (7-36)-NH2/(7-37), and its receptor GLP-1R; however, within minutes GLP-1 (7-36)-NH2/(7-37) becomes cleaved and inactivated by DPP4 into its smaller metabolite, GLP-1 (9-36)-NH2(9-37). It still remains unclear how GLP-1 (7-36)-NH2/(7-37), its metabolites, and GLP-1R provide beneficial vascular effects. We sought to elucidate the role of GLP-1 on vessel wall health using a novel in vitro human surrogate system that cocultures human endothelial (EC) and smooth muscle cells (SMCs) and applies human hemodynamics from the carotid bifurcation, a site prone to developing atherosclerosis, combined with other atherogenic factors (oxidized LDL, TNFα). Though, we found GLP-1R to be highly expressed in ECs and SMCs from both healthy and advanced inflammatory vascular environments, atheroprotective effects from the addition of GLP-1 (7-36)-NH2 or (9-36)-NH2 acted primarily on SMCs. In SMCs from atherogenic hemodynamic conditions, GLP-1 (7-36)-NH2 reduced NFkB activity and increased the anti-oxidant response protein, HO-1, via GLP-1R. A novel finding was that the cleaved metabolite, GLP-1 (9-36)-NH2, elicited the same response. Though GLP-1 (9-36)-NH2 did not alter downstream inflammatory gene expression, the NFkB-dependent pathways converged on pro-survival signaling since the metabolite GLP-1 (9-36)-NH2 uniquely decreased apoptotic signaling, including cleaved Caspase-3. These same responses were not seen with cleavage-resistant forms of GLP-1 (7-36)-NH2, but were rescued by adding back the cleavage product, (9-36)-NH2_further illustrating the distinct role of GLP-1 (9-36)-NH2 in promoting cell survival. This suggests future therapeutics would benefit by combining native GLP-1 along with its cleavage product, GLP-1 (9-36)-NH2. These findings demonstrate the novel effect of native GLP-1 and its cleavage-products on vessel wall health and provide new insights into creating more effective GLP-1 therapeutics for treatment of atherosclerosis and diabetes.