H₂S regulation of iron homeostasis by IRP1 improves vascular smooth muscle cell functions

Either H₂S or iron is essential for cellular processes. Abnormal metabolism of H₂S and iron has increased risk for cardiovascular diseases. The aim of the present study is to examine the mutual interplay of iron and H₂S signals in regulation of vascular smooth muscle cell (SMC) functions. Here we found that deficiency of cystathionine gamma-lyase (CSE, a major H₂S-producing enzyme in vascular system) induced but NaHS (a H₂S 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 H₂S 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 H₂S generation, while iron also non-enzymatically induced H₂S release from cysteine. This study reveals the mutual interaction between iron and H₂S signals in regulating SMC phenotypes and functions; CSE/H₂S system would be a target for preventing iron metabolic disorder-related vascular diseases.