Int J Biol Sci 2013; 9(7):656-665. doi:10.7150/ijbs.5887 This issue
Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing City 400038, P. R. China.
Angiogenesis plays an important role in myocardial repair after myocardial infarction (MI). Cardiac micro-vascular endothelial cells (CMECs) are important participants in myocardial angiogenesis processes. Recent studies have revealed that Nuclear factor-erythroid 2-related factor 2 (Nrf2), a master transcription factor of endogenous anti-oxidative defense systems, exerts cardio-protection in the cardiovascular system. However, the role of Nrf2 in the process of myocardial angiogenesis and corresponding mechanisms are not fully understood. Thus, the present study investigated the role of Nrf2 in the angiogenesis of rat CMECs to hypoxia. Trans-well assay, three-dimensional Matrigel assay were used to determine cell migration and vascular tube formation. Real-time RT-PCR, ELISA and Western blot were measured mRNA and protein expression. Here, we report that the mRNA and protein expression of Nrf2 and heme oxygenase-1(HO-1) were temporarily upregulated under hypoxic condition. Furthermore, knock down of Nrf2 significantly suppressed the migration and vascular tube formation of rat CMECs to hypoxia, Nrf2 knockdown also significantly decreased HO-1 and vascular endothelial growth factor (VEGF) expression at 48 h after transfection under hypoxic condition. Finally, transfection of CMECs with the Nrf2 over-expressing lentiviral vector upregulated HO-1 expression with a concomitant increase in cell migration and vascular tube formation induced by hypoxia, and this effect was greatly attenuated in the presence of ZnPP (a HO-1 inhibitor). Taken together, these results suggest that Nrf2 may mediate the angiogenesis of CMECs under hypoxic condition, and HO-1 is involved in regulating the angiogenesis of CMECs through Nrf2. Therefore, Nrf2 is a potent regulator of hypoxia-condition mediated angiogenesis in CMECs, which may provide a therapeutic strategy for myocardial repair after MI.
Keywords: Angiogenesis, Cardiac microvascular endothelial cell, NF-E2-related factor 2, Hypoxia.