Endothelin-2/Vasoactive Intestinal Contractor: Regulation of Expression via Reactive Oxygen Species Induced by CoCl(2)2, and Biological Activities Including Neurite Outgrowth in PC12 Cells

This paper reviews the local hormone endothelin-2 (ET-2), or vasoactive intestinal contractor (VIC), a member of the vasoconstrictor ET peptide family, where ET-2 is the human orthologous peptide of the murine VIC. While ET-2/VIC gene expression has been observed in some normal tissues, ET-2 recently has been reported to act as a tumor marker and as a hypoxia-induced autocrine survival factor in tumor cells. A recently published study reported that the hypoxic mimetic agent CoCl(2) at 200 µM increased expression of the ET-2/VIC gene, decreased expression of the ET-1 gene, and induced intracellular reactive oxygen species (ROS) increase and neurite outgrowth in neuronal model PC12 cells. The ROS was generated by addition of CoCl(2) to the culture medium, and the CoCl(2)-induced effects were completely inhibited by the antioxidant N-acetyl cysteine. Furthermore, interleukin-6 (IL-6) gene expression was up-regulated upon the differentiation induced by CoCl2. These results suggest that expression of ET-2/VIC and ET-1 mediated by CoCl(2)-induced ROS may be associated with neuronal differentiation through the regulation of IL-6 expression. CoCl(2) acts as a pro-oxidant, as do Fe(II, III) and Cu(II). However, some biological activities have been reported for CoCl(2) that have not been observed for other metal salts such as FeCl(3), CuSO(4), and NiCl(2). The characteristic actions of CoCl(2) may be associated with the differentiation of PC12 cells. Further elucidation of the mechanism of neurite outgrowth and regulation of ET-2/VIC expression by CoCl(2) may lead to the development of treatments for neuronal disorders.