Abstract 337: Cytoglobin Promotes Cardiac Stem Cell Survival Against Oxidative Stress via the Upregulation of the NFkB/iNOS Signal Pathway and Nitric Oxide Production

Cardiac stem cells may serve in regenerative medicine to repair the infarcted heart. However, this approach is severely limited by the poor survival of donor cells. We previously showed that preconditioning human cardiac stem cells (hCSCs) with a nitric oxide (NO) donor enhanced cell survival through activation of survival signaling pathways. Recent studies suggest that the mammalian globin cytoglobin (CYGB) regulates NO metabolism and may regulate cell death. Therefore, the goal of the present study was to test the hypothesis that CYGB may serve important pro-survival functions in hCSCs. We found that CYGB is expressed in hCSCs, in the absence of any significant expression of myoglobin (MB), the primary hemoglobin expressed in adult cardiomyocytes. Through molecular approaches aimed at increasing or decreasing CYGB expression in hCSCs, we found that CYGB functions as a pro-survival factor in response to oxidative stress. This was associated with the upregulation of primary antioxidant systems such as peroxiredoxin 1 (PRDX1) and heme oxygenase-1 and anti-apoptotic factors, including BCL2, BCL-XL, and MCL1. Most significantly, we established that CYGB increased the expression of NFкB-dependent genes including iNOS (NOS2) and that iNOS-dependent NO production was required for a feedforward loop that maintains CYGB expression. Our study delineates for the first time a role for a globin in regulating hCSC survival and establishes novel mechanistic insights in the functional role of CYGB. It provides a rationale for the exploration of the CYGB pathway as a novel molecular target that can be used to enhance the effectiveness of stem cell therapy for ischemic heart disease.