Prolyl hydroxylase inhibitor dimethyloxalylglycine enhances mesenchymal stem cell survival.
Mesenchymal stem cell (MSC) transplantation is a promising approach in the therapy of ischemic heart or CNS diseases; however, the poor viability of MSCs after transplantation critically limits the efficacy of this new strategy. Prolyl hydroxylase inhibition followed by HIF-1alpha up-regulation participates in the regulation of apoptosis and cell survival, which have been shown in cancer cells and neurons. The role of prolyl hydroxylase inhibition by dimethyloxalylglycine (DMOG) in regulation of cell survival has not been investigated in MSCs. In the present investigation with MSCs, apoptosis and cell death induced by serum deprivation were assessed by caspase-3 activation and trypan blue staining, respectively. The mitochondrial apoptotic pathway and PI3K/Akt cell survival pathway were evaluated. DMOG significantly attenuated apoptosis and cell death of MSCs, stabilized HIF-1alpha and induced downstream glucose transport 1 (Glut-1) synthesis. DMOG treatment reduced mitochondrial cytochrome c release, nuclear translocation of apoptosis inducing factor (AIF), and promoted Akt phosphorylation. A specific PI3K inhibitor, wortmannin, blocked Akt phosphorylation and abrogated the beneficial effect of DMOG. These data suggest that the DMOG protection of MSCs may provide a novel approach to promote cell survival during cell stress.
Liu
Xian-Bao
XB
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Wang
Jian-An
JA
Ogle
Molly E
ME
Wei
Ling
L
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D000600:Amino Acids, Dicarboxylic; D011393:Procollagen-Proline Dioxygenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; C040947:oxalylglycine