Genistein inhibits oxidative stress and alleviates vascular remodeling in hypertension through the GSK3β/FYN/Nrf2 pathway

Abstract

Hypertension raises cardiovascular risk via vascular remodeling, worsened by oxidative stress-linked VSMC dysfunction. Genistein (Gen), an antioxidant isoflavone, protects against cardiovascular diseases, but its role in hypertensive remodeling is unclear. This study explores if Gen eases remodeling by inhibiting oxidative stress via the GSK3β/FYN/Nrf2 pathway. In vivo, spontaneously hypertensive rats (SHR) and normotensive WKY rats got Gen (10−20 mg·kg⁻¹·d⁻¹) or valsartan (Val) for 10 weeks; aortic tissues were tested for morphology (HE/Masson), proliferation (PCNA), migration (MMP2/9), oxidative stress (NOX4), and VSMC phenotype (α-SMA/OPN). In vitro, SHR/WKY VSMCs were treated with Gen (10−40 μmol·L⁻¹) to check proliferation (EdU), migration (scratch/Transwell), ROS, and Nrf2 markers. Network pharmacology predicts Gen inhibits vascular remodeling via reducing hypertension-related oxidative stress, verified by EdU, scratch, Transwell, and Western blot. Gen reduced SHR blood pressure, vascular wall thickness, and fibrosis, reversing PCNA, MMP2/9, NOX4, OPN overexpression and α-SMA underexpression. In VSMCs, it dose-dependently inhibited proliferation/migration, reduced ROS, and restored Nrf2 pathway activity. Network analysis found 52 shared targets, with GSK3β, FYN, Nrf2 as key nodes. Gen and pGSK3β inhibitor SNP reversed GSK3β/FYN overexpression and Nrf2 underexpression; Nrf2 inhibitor ML385 barely affected pGSK3β/FYN. Thus, Nrf2 may lie downstream of GSK3β and FYN. Gen inhibits oxidative stress injury in the aortic tissue of SHR rats through the GSK3β/FYN/Nrf2 pathway, thereby reducing vascular remodeling in hypertension, lowering blood pressure, and exerting a protective effect on vascular lesions in hypertension. These findings provide new experimental evidence for Gen as a potential therapeutic agent against hypertensive vascular remodeling.

Keywords

Hypertension vascular remodeling / Genistein / Oxidative stress / Network pharmacology / GSK3β

Funding

This work was supported by the Training Program of Tianshan Talents (Nos. 2024TSYCCX0113 and 0305-CZ003101), the National Natural Science Foundation of China (No. 82460088), the Science and Technology Program of XPCC (Nos. 2023ZD035, 2022ZD042 and 2023ZD031), and the Shihezi University Undergraduate Research Training Program Project (No. 20231014557).

Acknowledgments

We acknowledge the Key Laboratory of Xinjiang Endemic and Ethnic Diseases, the NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, and the Department of Physiology and Pathophysiology of Shihezi University School of Medicine for their support.

Conflict of interest

The authors declare no potential competing interests, including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.

Supporting information

Supporting information of this paper can be requested by sending E-mail to the corresponding author.

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