Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia

Tsubokawa T, Yagi K, Nakanishi C, Zuka M, Nohara A, Ino H, Fujino N, Konno T, Kawashiri M, Ishibashi-Ueda H, Nagaya N, Yamagishi M. Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. Am J Physiol Heart Circ Physiol 298: H1320-H1329, 2010. First published February 12, 2010; doi:10.1152/ajpheart.01330.2008.-Although mesenchymal stem cells (MSCs) have therapeutic potential for tissue injury, intolerance and poor cell viability limit their reparative capability. Therefore, we examined the impact of bone marrow-derived MSCs, in which heme oxygenase-1 (HO-1) was transiently overexpressed, on the repair of an ischemic myocardial injury. When MSCs and HO-1-overexpressed MSCs (MSCHO-1) were exposed to serum deprivation/hypoxia or H2O2-induced oxidative stress, MSCHO-1 exhibited increased resistance to cell apoptosis compared with MSCs (17 +/- 1 vs. 30 +/- 2%, P < 0.05) and were markedly resistant to cell death (2 +/- 1 vs. 32 +/- 2%, P < 0.05). Under these conditions, vascular endothelial growth factor (VEGF) production was 2.1-fold greater in MSCHO-1 than in MSCs. Pretreatment of MSCs and MSCHO-1 with phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt) pathway inhibitors such as LY-294002 (50 mu M) or wortmannin (100 nM) significantly decreased VEGF production. In a rat infarction model with MSCs or MSCHO-1 (5 x 10(6) +/- 0.1 x 10(6) cells/rat) transplantation, the number of TdT-mediated dUTP nick end-labeling-positive cells was significantly lower in the MSCHO-1 group than in the MSC group (12.1 +/- 1.0 cells/field vs. 26.5 +/- 2.6, P < 0.05) on the 4th day after cell transplantation. On the 28th day, increased capillary density associated with decreased infarction size was observed in the MSCHO-1 group (1,415 +/- 47/mm(2) with 21.6 +/- 2.3%) compared with those in the MSCs group (1,215 +/- 43/mm(2) with 28.2 +/- 2.3%, P < 0.05), although infarction size relative to area at risk was not different in each group at 24 h after transplantation. These results demonstrate that MSCHO-1 exhibit markedly enhanced antiapoptotic and anti-oxidative capabilities compared with MSCs, thus contributing to improved repair of ischemic myocardial injury through cell survival and VEGF production associated with the PI 3-kinase/Akt pathway.