Sulfiredoxin-1 Inhibits PDGF-BB-Induced Vascular Smooth Muscle Cell Proliferation and Migration by Enhancing the Activation of Nrf2/ARE Signaling

Abstract

Sulfiredoxin1 (Srxn1), an endogenous antioxidant protein, is involved in cardiovascular diseases. In this study, we aimed to investigate the role of Srxn1 in VSMCs and its molecular mechanism. The murine vascular smooth muscle cells MOVAS were treated with different doses of platelet-derived growth factor-BB (PDGF-BB); then, Srxn1 expression was detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. MTT and wound healing assay were used to examine the effect of Srxn1 on MOVAS cell proliferation and migration. Reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity in MOVAS cells were detected using corresponding commercial kits. Moreover, the expression of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2), and nuclear factor erythroid-2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling-related proteins was detected using western blot analysis. In our study, PDGF-BB dose-dependently increased Srxn1 expression in MOVAS cells, and Srxn1 expression was increased with time dependence in PDGF-BB-treated MOVAS cells. The knockdown of Srxn1 increased PDGF-BB-induced the proliferation, migration, ROS production, MDA level, and the protein expression of PCNA and MMP-2, as well as decreased SOD activity and the expression of Nrf2/ARE signaling-related proteins in PDGF-BB-stimulated MOVAS cells. However, the overexpression of Srxn1 showed the opposite results to those of knockdown of Srxn1. Moreover, the inhibitory effects of Srxn1 overexpression on PDGF-BB induced proliferation, migration, ROS production, and MDA level and the promotion of Srxn1 overexpression on PDGF-BB induced SOD activity were partially reversed by the knockdown of Nrf2. Srxn1 inhibited PDGF-BB-induced proliferation, migration, and oxidative stress through activating Nrf2/ ARE signaling.

Transcription factors: key regulatory targets of vascular smooth muscle cell in atherosclerosis

“…Ko et al find that NRF2, which could be activated by p38 mitogen-activated protein kinase, induces the activation of the anti-inflammatory signaling pathway NRF2/HO-1, and then inhibits the proliferation and migration of VSMCs in mouse aorta (Ko et al 2020). Jiang et al demonstrate that Sulfiredoxin1, an endogenous antioxidant protein, inhibits PDGF-BB-induced VSMC proliferation and migration via enhancing the activation of NRF2/ARE signaling (Jiang et al 2022a). In addition to the NRF2 signaling pathway, the expression of myocyte enhancer factor 2C (MEF2C) inhibits VSMC proliferation and migration.…”

Nrf2-Mediated Dichotomy in the Vascular System: Mechanistic and Therapeutic Perspective

“…Similarly, cinnamic aldehyde, an electrophilic Nrf2 activator, can inhibit VSMC growth and intimal hyperplasia after balloon injury in a rat model of diabetic restenosis [152]. In addition, such beneficial activation of Nrf2 is implicated in the potential efficacy of other plant extracts in treating vascular diseases, including prunella vulgaris, sulfiredoxin-1, and physalin B [103,151,[156][157][158][159][160]. Synthetic drugs have also been documented to activate the protective function of Nrf2 in VSMCs.…”

Identification of the ceRNA axis of circ_0000006/miR-483-5p/KDM2B in the progression of aortic aneurysm to aorta dissection

“…In the healthy vascular wall, contractile VSMCs can be converted into synthetic VSMCs in the presence of aortic trauma or chronic cardiovascular disease. This conversion is triggered by abnormal signaling from growth factors, such as platelet-derived growth factor (PDGF) (13)(14). The contractility of VSMCs is reduced, while the capacities of proliferation and migration are increased, leading to the de-differentiation, abnormal proliferation, and migration of VSMCs.…”