FNDC5 Attenuates Oxidative Stress and NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells via Activating the AMPK-SIRT1 Signal Pathway.

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.

• Authors: Bing Zhou, Yun Qiu, Nan Wu, Ai-Dong Chen, Hong Zhou, Qi Chen, Yu-Ming Kang, Yue-Hua Li, Guo-Qing Zhu
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2020 Pg. 6384803 ( 2020) ISSN: 1942-0994 [Electronic] United States
• PMID: 32509148 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Bing Zhou et al.

Chemical References

• FNDC5 protein, mouse
• Fibronectins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Angiotensin II
• Protein Kinases
• AMP-Activated Protein Kinase Kinases
• Sirtuin 1

Topics

• AMP-Activated Protein Kinase Kinases
• Angiotensin II (metabolism)
• Animals
• Aorta (pathology)
• Cell Line
• Disease Models, Animal
• Fibronectins (genetics, metabolism)
• Humans
• Hypertension (metabolism)
• Inflammasomes (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocytes, Smooth Muscle (metabolism, pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Oxidative Stress
• Protein Kinases (metabolism)
• Rats
• Signal Transduction
• Sirtuin 1 (metabolism)