Abstract
Vascular oxidative stress and inflammation play a major role in vascular diseases. This study was aimed at determining the protective roles of fibronectin type III domain-containing 5 (FNDC5) in angiotensin II- (Ang II-) induced vascular oxidative stress and inflammation and underlying mechanisms. Wild-type (WT) and FNDC5−/− mice, primary mouse vascular smooth muscle cells (VSMCs), and the rat aortic smooth muscle cell line (A7R5) were used in the present study. Subcutaneous infusion of Ang II caused more serious hypertension, vascular remodeling, oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in the aorta of FNDC5−/− mice than those of WT mice. Exogenous FNDC5 attenuated Ang II-induced superoxide generation, NADPH oxidase 2 (NOX2) and NLRP3 upregulation, mature caspase-1, and interleukin-1β (IL-1β) production in A7R5 cells. The protective roles of FNDC5 were prevented by SIRT-1 inhibitor EX527, AMPK inhibitor compound C, or integrin receptor inhibitor GLPG0187. FNDC5 attenuated the Ang II-induced inhibition in SIRT1 activity, SIRT1 protein expression, and AMPKα phosphorylation in A7R5 cells, which were prevented by compound C, EX527, and GLPG0187. FNDC5 deficiency deteriorated Ang II-induced oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in primary aortic VSMCs of mice, which were prevented by exogenous FNDC5. These results indicate that FNDC5 deficiency aggravates while exogenous FNDC5 alleviates the Ang II-induced vascular oxidative stress and NLRP3 inflammasome activation via the AMPK-SIRT1 signal pathway in VSMCs.
Highlights
Chronic vascular inflammation greatly contributes to the pathogeneses of hypertension, atherosclerosis, and aortic aneurysm [1,2,3]
Hypertension and vascular remodeling were induced by subcutaneous infusion of Angiotensin II (Ang II) with a microosmotic pump for 2 weeks in wild-type mice (WT) and fibronectin type III domain-containing 5 (FNDC5) knockout mice (KO)
FNDC5 deficiency had no significant effects on blood pressure in the PBS-treated mice but aggravated angiotensin II- (Ang II-)induced hypertension (Figure 1(a))
Summary
Chronic vascular inflammation greatly contributes to the pathogeneses of hypertension, atherosclerosis, and aortic aneurysm [1,2,3]. Accumulated studies in animals and humans have revealed a great contribution of inflammation to vascular oxidative stress [4,5,6]. Anti-inflammation therapies have protective effects in cardiovascular diseases, and normalization of oxidative stress is an essential characteristic of these therapies [7]. Oxidative stress represents excessive intracellular reactive oxygen species (ROS), which promotes inflammation, and greatly assists in the pathogenesis of cardiovascular diseases [8]. The ROS are important oxidative stressors implicated in driving vascular diseases by promoting vascular inflammation, increasing the proliferation, migration, and apoptosis of the vascular smooth muscle cells (VSMCs), and thereby stimulating vascular remodeling [9,10,11].
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