Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Oxid Med Cell Longev. 2020 May 16;2020:6384803. doi: 10.1155/2020/6384803. eCollection 2020.
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-1 (IL-1) 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 AMPK 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.
血管氧化应激和炎症在血管疾病中起着重要作用。本研究旨在确定纤维连接蛋白 III 型结构域 5（FNDC5）在血管紧张素 II（Ang II）诱导的血管氧化应激和炎症中的保护作用及其潜在机制。本研究使用了野生型（WT）和 FNDC5 小鼠、原代小鼠血管平滑肌细胞（VSMCs）和大鼠主动脉平滑肌细胞系（A7R5）。皮下注射 Ang II 导致 FNDC5 小鼠的高血压、血管重构、氧化应激、NLRP3 炎性体激活、AMPK 磷酸化抑制和 SIRT1 下调比 WT 小鼠更为严重。外源性 FNDC5 减轻了 Ang II 诱导的 A7R5 细胞中超氧化物生成、NADPH 氧化酶 2（NOX2）和 NLRP3 上调、成熟半胱天冬酶-1 和白细胞介素-1（IL-1）的产生。SIRT-1 抑制剂 EX527、AMPK 抑制剂化合物 C 或整合素受体抑制剂 GLPG0187 阻止了 FNDC5 的保护作用。FNDC5 减轻了 Ang II 诱导的 A7R5 细胞中 SIRT1 活性、SIRT1 蛋白表达和 AMPK 磷酸化的抑制，而化合物 C、EX527 和 GLPG0187 则阻止了这种抑制。FNDC5 缺乏加剧了 Ang II 诱导的氧化应激、NLRP3 炎性体激活、AMPK 磷酸化抑制和小鼠主动脉 VSMCs 中 SIRT1 的下调，而外源性 FNDC5 则阻止了这一过程。这些结果表明，FNDC5 缺乏加剧了 Ang II 诱导的血管氧化应激和 NLRP3 炎性体激活，而外源性 FNDC5 通过 AMPK-SIRT1 信号通路在 VSMCs 中减轻了这种作用。
