YC‐1 stimulates heme oxygenase‐1 gene expression in vascular smooth muscle cells

Abstract

The benzyl‐indazole derivative YC‐1 enhances the biological actions of heme oxygenase (HO) in vascular smooth muscle cells (SMC) by sensitizing soluble guanylate cyclase (sGC) to the stimulatory effect of HO‐derived carbon monoxide (CO). However, the regulatory impact of YC‐1 on HO and/or CO is not known. In this study, the effect on YC‐1 on HO‐1 expression was investigated in rat cultured aortic SMC. Treatment of SMC with YC‐1 (5‐100μM) stimulated HO‐1 protein expression in a time and concentration‐dependent manner. A significant rise in HO‐1 protein was first detected after 4 hours and HO‐1 levels progressively increased over 24 hours of YC‐1 exposure. Increases in HO‐1 protein were preceded by marked elevations in HO‐1 mRNA, and transient transfection experiments showed that YC‐1 stimulated HO‐1 promoter activity approximately 2‐fold. Interestingly, the induction of HO‐1 by YC‐1 was unchanged by the sGC inhibitor ODQ or by the protein kinase G inhibitor KT5823. Moreover, YC‐1‐mediated HO‐1 induction was not duplicated by the NO‐independent sGC stimulator, BAY 41‐2272. In conclusion, this study demonstrates that YC‐1 stimulates the transcriptional activation of the HO‐1 gene in a cGMP‐independent fashion. The distinct ability of YC‐1 to amplify the beneficial vascular effects of CO at both the level of CO synthesis and cellular response underscores the therapeutic potential of this agent. Supported by NIH.