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.

Progress and Challenges in the Biology of FNDC5 and Irisin

“…In another study, using a separately derived FNDC5 KO, Xiong et al ( 95 ) observed that the high fat diet also induced obesity and insulin resistance, which were exacerbated in the KO mice. Zhou et al ( 160 ) also induced vascular oxidative stress and inflammation by injecting angiotensin II. The effects were aggravated by the absence of FNDC5.…”

Interleukin-1β in Multifactorial Hypertension: Inflammation, Vascular Smooth Muscle Cell and Extracellular Matrix Remodeling, and Non-Coding RNA Regulation

“…It was demonstrated that miR-340-5p inversely correlated with IL-1β and IL-6 levels in acute pulmonary embolism patients with PH. miRNA340-5p also dampened the level of SMC proliferation and migration, likely by suppressing the activities of IL-1β and IL-6 [53].…”

“…In addition, blocking NLRP3 with fibronectin type III domain-containing 5 (FNDC5) reduced not only oxidative stress, NLRP3 activity, and vascular remodeling in VSMCs but also modulated Amp-activated protein kinase (AMPK)-histone/protein deacetylase Sirtuin1 (SIRT1) activity, a known interaction that plays a role in energy metabolism. This group demonstrated that NLRP3/ IL-1β could influence VSMC function through an AMPK-SIRT1 dependent mechanism influenced by metabolic homeostasis [53].…”

The Role of Glycocalyx and Caveolae in Vascular Homeostasis and Diseases

“…In VSMCs, ROS production is mediated especially by NOX1 and NOX4 and produces O 2 – and H 2 O 2 , respectively ( Burtenshaw et al, 2019 ). Increased ROS in VSMCs is a common feature of different models of hypertension such as AngII-infused model ( Rajagopalan et al, 1996 ; Zhou et al, 2020 ), spontaneously hypertensive rats (SHR) ( Graton et al, 2019 ), renovascular hypertension (2K-1C) ( Castro et al, 2012 ; Oliveira-Paula et al, 2016 ), and Doca-Salt rats ( Amaral et al, 2015 ). Physiologically, contraction mediated by activation of α-1 adrenoceptors can partially depend on O 2 – ( Tsai and Jiang, 2010 ).…”