Arif Hassan Mustafa, Fu Ming, Wang Rui
Department of Biology, York University, Toronto, ON M3J 1P3, Canada.
College of Basic Medicine, Shandong Second Medical University, Weifang 261053, China.
Antioxidants (Basel). 2025 May 8;14(5):560. doi: 10.3390/antiox14050560.
Iron overload contributes to proliferative vascular diseases, yet its interplay with hydrogen sulfide (HS) in vascular smooth muscle cell (VSMC) proliferation remains poorly understood. This study elucidates HS's role in mitigating iron-overload-induced oxidative stress and cellular damage. Using aortic VSMCs from wildtype (WT) and cystathionine γ-lyase-knockout (CSE-KO) mice treated with ferric ammonium citrate (FAC) at concentrations equivalent to serum levels of iron and citrate, we demonstrate that FAC triggers the integrated stress response (ISR) in WT cells, upregulating CSE to enhance HS production. The ISR mediator ATF4 activates caspases but simultaneously induces CSE, which inhibits caspase activity and promotes autophagy via AMPK signaling. In CSE-KO cells, iron overload leads to diminished Ferritin upregulation, unchecked Caspase activation, and impaired autophagy compared to WT cells. Exogenous HS restored iron homeostasis by enhancing Ferritin expression, activating NRF2 antioxidant pathways, and restoring apoptosis-autophagy equilibrium in both WT and KO cells. These findings establish HS as a critical regulator of iron-induced VSMC dysfunction, highlighting its therapeutic potential in managing vascular pathologies linked to iron dysregulation.
铁过载会导致增殖性血管疾病，但其在血管平滑肌细胞（VSMC）增殖过程中与硫化氢（HS）的相互作用仍知之甚少。本研究阐明了HS在减轻铁过载诱导的氧化应激和细胞损伤中的作用。使用来自野生型（WT）和胱硫醚γ-裂解酶基因敲除（CSE-KO）小鼠的主动脉VSMC，用相当于血清中铁和柠檬酸盐水平的柠檬酸铁铵（FAC）处理，我们证明FAC在WT细胞中触发整合应激反应（ISR），上调CSE以增强HS的产生。ISR介质ATF4激活半胱天冬酶，但同时诱导CSE，CSE通过AMPK信号通路抑制半胱天冬酶活性并促进自噬。与WT细胞相比，在CSE-KO细胞中，铁过载导致铁蛋白上调减少、半胱天冬酶激活不受控制和自噬受损。外源性HS通过增强铁蛋白表达、激活NRF2抗氧化途径以及恢复WT和KO细胞中的凋亡-自噬平衡来恢复铁稳态。这些发现确立了HS作为铁诱导的VSMC功能障碍的关键调节因子，突出了其在治疗与铁失调相关的血管疾病中的治疗潜力。
