Redox report : communications in free radical research · 2026
γ-Glutamylcysteine alleviates hypertension and vascular remodeling in SHR by suppressing oxidative stress through Keap1 S-glutathionylation.
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Lei Jianzhen, Kong Yueru, Ye Chao, Zhang Chuanyue, Shen Yi, Wu Xin, Wu Qiuyue, Han Ying, Chen Min, Song Yueqi, Yan Qing, Zheng Fen, Xia Xinyi
Аннотация
OBJECTIVES: Pathological arterial remodeling heavily depends on the aberrant proliferation and migration of vascular smooth muscle cells (VSMCs). This study explores how γ-Glutamylcysteine (γ-GC) regulates VSMC signaling to mitigate hypertensive structural damage.
METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats received intraperitoneal injections of γ-GC (100 mg/kg) every two days for 4 weeks. Blood pressure and arterial remodeling were evaluated. Primary aortic VSMCs were cultured for cellular mechanism analysis. To verify Nrf2 pathway requirement, the Nrf2 inhibitor ML385 was applied in vitro and via osmotic pumps in vivo.
RESULTS: γ-GC lowered systemic blood pressure and prevented arterial medial thickening in SHR, while normotensive controls remained unaffected. In SHR-VSMCs, γ-GC inhibited cell migration, proliferation, and phenotypic switching, and alleviated cellular oxidative stress. RNA-seq revealed significant enrichment of the Nrf2 signaling pathway. Mechanistically, γ-GC induced Keap1 S-glutathionylation, which disrupted the Keap1 and Nrf2 interaction and promoted Nrf2 nuclear translocation. Notably, Nrf2 inhibition with ML385 abolished the protective effects of γ-GC in vivo and in vitro.
DISCUSSION: γ-GC attenuates hypertensive arterial remodeling by modulating intracellular signaling, specifically through Keap1 S-glutathionylation-dependent Nrf2 activation. The Keap1/Nrf2 signaling axis is required for γ-GC to restore VSMC function, suggesting a targeted molecular mechanism for cardiovascular protection.
METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats received intraperitoneal injections of γ-GC (100 mg/kg) every two days for 4 weeks. Blood pressure and arterial remodeling were evaluated. Primary aortic VSMCs were cultured for cellular mechanism analysis. To verify Nrf2 pathway requirement, the Nrf2 inhibitor ML385 was applied in vitro and via osmotic pumps in vivo.
RESULTS: γ-GC lowered systemic blood pressure and prevented arterial medial thickening in SHR, while normotensive controls remained unaffected. In SHR-VSMCs, γ-GC inhibited cell migration, proliferation, and phenotypic switching, and alleviated cellular oxidative stress. RNA-seq revealed significant enrichment of the Nrf2 signaling pathway. Mechanistically, γ-GC induced Keap1 S-glutathionylation, which disrupted the Keap1 and Nrf2 interaction and promoted Nrf2 nuclear translocation. Notably, Nrf2 inhibition with ML385 abolished the protective effects of γ-GC in vivo and in vitro.
DISCUSSION: γ-GC attenuates hypertensive arterial remodeling by modulating intracellular signaling, specifically through Keap1 S-glutathionylation-dependent Nrf2 activation. The Keap1/Nrf2 signaling axis is required for γ-GC to restore VSMC function, suggesting a targeted molecular mechanism for cardiovascular protection.