Protective Effect of S-Adenosyl-L-Methionine on Oxidative Stress-Induced Apoptosis Regulates Nrf-2 via IGF-I in Rat Bone Marrow Mesenchymal Stem Cells

Abstract

Bone marrow mesenchymal stem cell (MSC)-mediated regeneration is a promising treatment for degenerative diseases and traumatic injuries. S-Adenosyl-L-methionine (SAM) is the principal biological methyl donor. We hypothesized that the cytoprotective effect of SAM on oxidative stress-induced apoptosis in rat MSCs is due to insulin-like growth factor-I (IGF-I) and nuclear factor erythroid 2-related factor 2 (Nrf2). SAM (10 µM) increased both endogenous IGF-I levels and cell viability (p<0.05). In MSCs, 1 mM H 2 O 2 at 6 h significantly decreased cell viability and IGF-I and Nrf2 activation, but increased ROS generation (p<0.05 and p<0.01, respectively). The decrease in cell viability, endogenous IGF-1, and Nrf2 in H 2 O 2-induced apoptosis was recovered by SAM (10 µM). Apoptosis induced by H 2 O 2 also decreased Nrf2 activity, as determined by immunofluorescence staining, but the decrease was also recovered by SAM. We demonstrated that H 2 O 2-induced apoptosis was reduced by SAM through Annexin-V. Using a specific small interfering RNA (siRNA), the increase in SAM-induced cell viability and endogenous Nrf2 in the presence of H 2 O 2 was suppressed by IGF-I siRNA, but the endogenous IGF-I level was not changed by Nrf2 siRNA. The increase in endogenous Nrf2 with exogenous IGF-I and H 2 O 2 treatment was also suppressed by Nrf2 siRNA, but the IGF-I level was not inhibited (p<0.05). These results suggest that the cytoprotective effect of SAM against H 2 O 2induced apoptosis is mediated by increased Nrf2 activity through IGF-I. These factors could regulate the metabolic fate and survival of MSCs.