Abstract 8993: Protective Effects of Glucagon-like Peptide-1 on Cardiac Microvessels Injury via cAMP/PKA/Rho Dependent Pathway in Diabetic Rats

Abstract

Introduction: Impaired cardiac microvascular function contributes greatly to diabetes cardiovascular disease. Glucagon-like peptide-1 (GLP-1) was found to have multiple cardioprotective effects besides its glucose lowering properties. Hypothesis: To investigate the protective effects of GLP-1 on cardiac microvessels injury and the underlying mechanism in diabetic rats. Methods: STZ-induced diabetic rats were randomized to 12 weeks of treatment with vehicle, LAF237 or Exenatide. Cardiac function and energetics was examined by echocardiography and 18 F-FDG PET respectively. Lanthanum nitrate perfusion was applied to assess cardiac microvascular barrier function. Cardiac microvascular endothelial cells (CMECs) were cultured in medium alone or medium containing high glucose, GLP-1, high glucose plus GLP-1. Lucigenin-enhanced chemiluminescence assay and DHE staining were used to assess ROS production. The expression of Rho, ROCK, p47 phox and gp91 phox was examined by Western blot. Results: LAF237 or Exetinade treatment improved cardiac function and energetics as well as microvascular barrier function significantly compared with vehicle groups. Compared with vehicle groups, ROS production was markedly decreased in GLP-1 groups. There were also significant reductions in p47 phox and gp91 phox expression. The cAMP/PKA activity was increased and the Rho expression was decreased in high glucose-induced CMECs after treatment with GLP-1, which reproduced the same effects as PKA inhibitor. Conclusions: GLP-1 could protect the cardiac microvessels against oxidative stress injury and the resultant microvascular barrier dysfunction in diabetic rats, which contribute to the improvement of cardiac function. The protective effects of GLP-1 are dependent on downstream inhibition of Rho, which is through cAMP/PKA pathway, resulting in subsequent decreased production of NADPH oxidase.