School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.
School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.
Cell Signal. 2023 Oct;110:110826. doi: 10.1016/j.cellsig.2023.110826. Epub 2023 Jul 23.
Either HS or iron is essential for cellular processes. Abnormal metabolism of HS and iron has increased risk for cardiovascular diseases. The aim of the present study is to examine the mutual interplay of iron and HS signals in regulation of vascular smooth muscle cell (SMC) functions. Here we found that deficiency of cystathionine gamma-lyase (CSE, a major HS-producing enzyme in vascular system) induced but NaHS (a HS donor) administration attenuated iron accumulation in aortic tissues from angiotensin II-infused mice. In vitro, iron overload induced labile iron levels, promoted cell proliferation, disrupted F-actin filaments, and inhibited protein expressions of SMC-specific markers (αSMA and calponin) more significantly in SMCs from CSE knockout mice (KO-SMCs) than the cells from wild-type mice (WT-SMCs), which could be reversed by exogenously applied NaHS. In contrast, KO-SMCs were more vulnerable to iron starvation-induced cell death. Either iron overload or NaHS did not affect elastin level and gelatinolytic activity. We further found that HS induced more aconitase activity of iron regulatory protein 1 (IRP1) but inhibited its RNA binding activity accompanied with increased protein levels of ferritin and ferriportin, which would contribute to the lower level of labile iron level inside the cells. In addition, iron was able to suppress CSE-derived HS generation, while iron also non-enzymatically induced HS release from cysteine. This study reveals the mutual interaction between iron and HS signals in regulating SMC phenotypes and functions; CSE/HS system would be a target for preventing iron metabolic disorder-related vascular diseases.
无论是 HS 还是铁，对于细胞过程都是必不可少的。 HS 和铁的代谢异常会增加心血管疾病的风险。本研究旨在探讨铁和 HS 信号在调节血管平滑肌细胞 (SMC) 功能中的相互作用。在这里，我们发现胱硫醚γ-裂解酶 (CSE，血管系统中主要的 HS 产生酶) 缺乏会诱导，但 NaHS (HS 供体) 给药会减轻血管紧张素 II 输注小鼠主动脉组织中铁的积累。在体外，铁过载诱导不稳定铁水平，促进细胞增殖，破坏 F-肌动蛋白丝，并显著抑制 CSE 敲除小鼠 (KO-SMCs) 而非野生型小鼠 (WT-SMCs) 中 SMC 特异性标志物 (αSMA 和 calponin) 的蛋白表达，这可以通过外源性 NaHS 逆转。相反，KO-SMCs 对铁饥饿诱导的细胞死亡更为敏感。铁过载或 NaHS 均不影响弹性蛋白水平和明胶酶活性。我们进一步发现， HS 诱导铁调节蛋白 1 (IRP1) 的 aconitase 活性增加，但抑制其 RNA 结合活性，伴随着铁蛋白和铁输出蛋白的蛋白水平增加，这将导致细胞内不稳定铁水平降低。此外，铁能够抑制 CSE 衍生的 HS 生成，而铁也能够非酶促地从半胱氨酸中诱导 HS 释放。本研究揭示了铁和 HS 信号在调节 SMC 表型和功能中的相互作用；CSE/HS 系统可能是预防与铁代谢紊乱相关的血管疾病的靶点。
