Suppression of angiotensin II-activated NOX4/NADPH oxidase and mitochondrial dysfunction by preserving glucagon-like peptide-1 attenuates myocardial fibrosis and hypertension

This study aims to investigate whether stabilization of glucagon-like peptide-1 (GLP-1) level reduces angiotensin II (Ang II)-induced cardiac fibrosis and-elevated blood pressure accompanying with inhibition of NADPH oxi-dase (NOX) expression and preservation of mitochondrial integrity. The study was performed in Sprague-Dawley rat model of Ang II infusion (500 ng/kg/min) using osmotic minipumps for 4 weeks. GLP-1 receptor agonist liraglutide (0.3 mg/kg, injected subcutaneously twice daily) and dipeptidyl peptides-4 inhibitor, linagliptin (8 mg/kg, administered via oral gavage) were selected to preserve GLP-1 level. Blood pressure was measured noninvasively. Heart and aorta were saved for histological analysis. Relative to the animals with Ang II infusion, in the heart, liraglutide and linagliptin comparatively reduced the protein levels of NOX4 and TGF beta 1 and expression of monocyte chemoattractant protein 1, and attenuated the proliferation of myofibroblasts (15 +/- 4 and 13 +/- 3 vs. 42 +/- 22/HPF in Ang II group). The number of distorted mitochondria in both groups was significantly reduced (8 +/- 4 and 10 +/- 6 vs. 27 +/- 13/HPF in Ang II group), in company with a significant reduction in cardiac fibrosis. In the aorta, treatment with liraglutide and linagliptin significantly downregulated the expression of NOX4 and intercellular adhesion molecule 1, and enhanced endothelial NOS expression. Aortic wall thickness was reduced comparatively (267 +/- 22 and 286 +/- 25 vs. 339 +/- 40 mu m in Ang II group). The area of fibrotic aorta was also reduced (13 +/- 6 and 14 +/- 5 vs. 38 +/- 24 mm(2) in Ang II group), respectively, in coinci-dence with a significant reduction in mean blood pressure. Taken together, these results suggest that the con-servation of GLP-1 level with exogenous supply of liraglutide or the prevention of endogenous degradation of GLP-1 with linagliptin protects against Ang II-induced injury in the heart and aorta, potentially associated with inhibition of NOX4 expression and preservation of mitochondrial integrity.

Automated summary

This study found that stabilizing GLP-1 levels can reduce Ang II-induced cardiac fibrosis and high blood pressure by inhibiting NOX4 expression and preserving mitochondrial integrity.