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

Abstract

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.

• Authors: Toshinari Tsubokawa, Kunimasa Yagi, Chiaki Nakanishi, Masahiko Zuka, Atsushi Nohara, Hidekazu Ino, Noboru Fujino, Tetsuo Konno, Masa-aki Kawashiri, Hatsue Ishibashi-Ueda, Noritoshi Nagaya, Masakazu Yamagishi
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 298 Issue 5 Pg. H1320-9 (May 2010) ISSN: 1522-1539 [Electronic] United States
• PMID: 20154257 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Serum-Free
• Cytokines
• Phosphoinositide-3 Kinase Inhibitors
• Vascular Endothelial Growth Factor A
• RNA
• Heme Oxygenase-1
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (physiology)
• Bone Marrow Transplantation
• Capillaries (pathology)
• Cell Differentiation
• Cell Lineage
• Cell Survival
• Culture Media, Serum-Free
• Cytokines (metabolism)
• Heme Oxygenase-1 (biosynthesis)
• Male
• Mesenchymal Stem Cell Transplantation
• Myocardial Ischemia (diagnostic imaging, pathology, therapy)
• Oxidative Stress (physiology)
• Phenotype
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• RNA (biosynthesis, isolation & purification)
• Rats
• Rats, Inbred Lew
• Reverse Transcriptase Polymerase Chain Reaction
• Ultrasonography
• Vascular Endothelial Growth Factor A (metabolism)