Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia.
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 (MSC(HO-1)) were exposed to serum deprivation/hypoxia or H(2)O(2)-induced oxidative stress, MSC(HO-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 MSC(HO-1) than in MSCs. Pretreatment of MSCs and MSC(HO-1) with phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt) pathway inhibitors such as LY-294002 (50 muM) or wortmannin (100 nM) significantly decreased VEGF production. In a rat infarction model with MSCs or MSC(HO-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 MSC(HO-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 MSC(HO-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 MSC(HO-1) exhibit markedly enhanced anti-apoptotic 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.
Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Takara-machi 13-1, Kanazawa, Ishikawa, Japan.
Toshinari
T
Tsubokawa
Kunimasa
K
Yagi
Chiaki
C
Nakanishi
Masahiko
M
Zuka
Atsushi
A
Nohara
Hidekazu
H
Ino
Noboru
N
Fujino
Tetsuo
T
Konno
Masa-aki
MA
Kawashiri
Hatsue
H
Ishibashi-Ueda
Noritoshi
N
Nagaya
Masakazu
M
Yamagishi
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000473:pathology; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D018384:Oxidative Stress / Q000502:physiology*; D010641:Phenotype; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016895:Culture Media, Serum-Free; D016207:Cytokines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt