Browsing Research, Student by Author "Banks, Trenton"
Reduction Of Angiotensin Ii Induced Hypertension And Cardiac Fibrosis With Glp-1 Receptor Agonist And Dpp-4 Inhibitor Via Decreasing Nadph Oxidase ExpressionBanks, TrentonObjectives: Preservation of plasma glucagon-like peptide-1 (GLP-1) has been demonstrated to be cardioprotective in animals and patients. This study aims to investigate the mechanisms of action underlying cardioprotection by enhancing GLP-1 level through inhibiting NADPH oxidase mediated signaling. Methods: The study was performed in the Sprague-Dawley rat model of angiotensin II (Ang II) infusion (500 ng/kg/min) using osmotic minipumps for 4 weeks. GLP-1 agonist liraglutide (0.3 mg/kg, injected subcutaneously twice daily) and dipeptidyl peptidease-4 inhibitor, linagliptin (8 mg/kg, administered via oral gavage) were selected to preserve GLP-1 level. Blood pressure was measured noninvasively. Aorta and heart were saved for histological analysis. Results: Relative to the animals with Ang II infusion, in the aorta, treatment with liraglutide and linagliptin significantly downregulated the expression of NOX4/ICAM-1, and enhanced eNOS expression. Aortic wall thickness was reduced comparatively (267.4 ±22.5µm and 286.6 ±25.5µm vs. 339.7 ±40.4µm in Ang II group, all p＜0.05); with a significant reduction in mean blood pressure in these two groups (121±19 and 139±16 mmHg vs. 163±30 mmHg in Ang II group, all p<0.05). In the heart, liraglutide and linagliptin comparatively reduced the protein levels of NOX4 and TGFβ1 and expression of MCP-1, as well as attenuated the proliferation of myofibroblasts (15.1±4.9 and 13.3±3.6 vs. 42.8±22.6/HPF in Ang II group, all p<0.05). Furthermore, mitochondrial structure damaged by Ang II was significantly preserved by liraglutide and linagliptin, in company with a significant reduction in cardiac fibrosis. Conclusion: Taken together, these results suggest that the preservation of GLP-1 level with exogenous supply of GLP-1 with liraglutide or prevention of endogenous degradation of GLP-1 with linagliptin protects against Ang II induced injury in aorta and heart, primarily mediated by inhibiting NOX-mediated signaling.