Protective effect of a hydrogen sulfide donor on balloon injury-induced restenosis via the Nrf2/HIF-1α signaling pathway.

Abstract

Restenosis is liable to occur following treatment with endovascular interventional therapy. Increasing evidence indicates that hydrogen sulfide (H2S) exhibits numerous physiological properties, including antioxidative and cardioprotective disease properties. Thus, the present study aimed to investigate the anti-restenosis effects of H2S and its protective mechanisms. A balloon dilatation restenosis model was used, in which model Sprague-Dawley rats were treated with sodium hydrosulfide (NaHS: A donor of H2S, 30 µmol/kg) by intraperitoneal injection for 4 weeks. Histological observations of the carotid artery were performed, and H2S production and the expression of Nuclear factor-E2-related factor 2 (Nrf2)/hypoxia-inducible factor (HIF)-1α signaling pathway proteins were measured. In addition, human umbilical vein endothelial cells (HUVECs) were treated with NaHS following the inhibition of Nrf2 or HIF-1α expression. The expression of Nrf2/HIF-1α signaling pathway proteins, tube formation and cell migration were evaluated thereafter. The results demonstrated that NaHS treatment significantly increased H2S production in rats with restenosis, and that neointimal thickness decreased significantly in arteries with restenosis. Furthermore, an increase in H2S production enhanced the nuclear accumulation of Nrf2 and expression of its downstream targets, heme oxygenase-1 and superoxide dismutase, as well as HIF-1α. Similar effects of NaHS on the expression of these proteins were observed in HUVECs. Additionally, these findings indicated that NaHS-induced HIF-1α expression was dependent on Nrf2 expression. NaHS treatment also markedly increased tube formation by upregulating vascular endothelial growth factor expression and cell migration, both of which were mediated by the Nrf2/HIF-1α signaling pathway, and suppressed the migration and proliferation of human vascular smooth muscle cells. Thus, NaHS-mediated H2S production was observed to prevent neointimal hyperplasia, promote activation of the Nrf2/HIF-1α signal pathway, and enhance HUVEC tube formation and migration, thereby exerting protective effects on balloon injury-induced restenosis.