Hypoxia stimulates the expression of macrophage migration inhibitory factor in human vascular smooth muscle cells via HIF-1alpha dependent pathway.

BACKGROUND

Hypoxia plays an important role in vascular remodeling and directly affects vascular smooth muscle cells (VSMC) functions. Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor, and recent evidence suggests an important role of MIF in the progression of atherosclerosis and restenosis. However, the potential link between hypoxia and MIF in VSMC has not been investigated. The current study was designed to test whether hypoxia could regulate MIF expression in human VSMC. The effect of modulating MIF expression on hypoxia-induced VSMC proliferation and migration was also investigated at the same time.

RESULTS

Expression of MIF mRNA and protein was up-regulated as early as 2 hours in cultured human VSMCs after exposed to moderate hypoxia condition (3% O2). The up-regulation of MIF expression appears to be dependent on hypoxia-inducible transcription factor-1alpha(HIF-1alpha) since knockdown of HIF-1alpha inhibits the hypoxia induction of MIF gene and protein expression. The hypoxia induced expression of MIF was attenuated by antioxidant treatment as well as by inhibition of extracellular signal-regulated kinase (ERK). Under moderate hypoxia conditions (3% O2), both cell proliferation and cell migration were increased in VSMC cells. Blocking the MIF by specific small interference RNA to MIF (MIF-shRNA) resulted in the suppression of proliferation and migration of VSMCs.

CONCLUSION

Our results demonstrated that in VSMCs, hypoxia increased MIF gene expression and protein production. The hypoxia-induced HIF-1alpha activation, reactive oxygen species (ROS) generation and ERK activation might be involved in this response. Both MIF and HIF-1alpha mediated the hypoxia response of vascular smooth muscle cells, including cell migration and proliferation.