Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, GA, USA.
Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, GA, USA.
Eur J Pharmacol. 2022 Jul 15;927:175048. doi: 10.1016/j.ejphar.2022.175048. Epub 2022 May 26.
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 oxidase (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 TGFβ1 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 μm in Ang II group). The area of fibrotic aorta was also reduced (13 ± 6 and 14 ± 5 vs. 38 ± 24 mm in Ang II group), respectively, in coincidence with a significant reduction in mean blood pressure. Taken together, these results suggest that the conservation 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.
本研究旨在探讨胰高血糖素样肽-1（GLP-1）水平的稳定是否通过抑制 NADPH 氧化酶（NOX）表达和维持线粒体完整性来减少血管紧张素 II（Ang II）诱导的心肌纤维化和血压升高。该研究使用渗透微型泵在 Ang II 输注（500ng/kg/min）的 Sprague-Dawley 大鼠模型中进行了 4 周。选择 GLP-1 受体激动剂利拉鲁肽（0.3mg/kg，皮下注射，每日两次）和二肽基肽酶-4 抑制剂利格列汀（8mg/kg，口服灌胃）来维持 GLP-1 水平。非侵入性测量血压。保存心脏和主动脉进行组织学分析。与 Ang II 输注组相比，利拉鲁肽和利格列汀在心脏中降低了 NOX4 和 TGFβ1 的蛋白水平和单核细胞趋化蛋白 1 的表达，并减弱了肌成纤维细胞的增殖（15±4 和 13±3 与 Ang II 组的 42±22/HPF）。两组中扭曲的线粒体数量明显减少（8±4 和 10±6 与 Ang II 组的 27±13/HPF），同时心脏纤维化明显减少。在主动脉中，利拉鲁肽和利格列汀的治疗显著下调了 NOX4 和细胞间黏附分子 1 的表达，并增强了内皮型一氧化氮合酶的表达。主动脉壁厚度明显变薄（267±22 和 286±25 与 Ang II 组的 339±40μm）。纤维化主动脉的面积也分别减少（13±6 和 14±5 与 Ang II 组的 38±24mm），同时平均血压显著降低。综上所述，这些结果表明，外源性给予利拉鲁肽或用利格列汀防止 GLP-1 的内源性降解来维持 GLP-1 水平可防止 Ang II 诱导的心脏和主动脉损伤，可能与抑制 NOX4 表达和维持线粒体完整性有关。
