Wang Xian-Yun, Fan Xue-Song, Cai Lin, Liu Si, Cong Xiang-Feng, Chen Xi
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Centre for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
Apoptosis. 2015 Mar;20(3):273-84. doi: 10.1007/s10495-014-1074-0.
The increase of reactive oxygen species in infracted heart significantly reduces the survival of donor mesenchymal stem cells, thereby attenuating the therapeutic efficacy for myocardial infarction. In our previous study, we demonstrated that lysophosphatidic acid (LPA) protects bone marrow-derived mesenchymal stem cells (BMSCs) against hypoxia and serum deprivation-induced apoptosis. However, whether LPA protects BMSCs from H2O2-induced apoptosis was not examined. In this study, we report that H2O2 induces rat BMSC apoptosis whereas LPA pre-treatment effectively protects BMSCs from H2O2-induced apoptosis. LPA protection of BMSC from the induced apoptosis is mediated mostly through LPA3 receptor. Furthermore, we found that membrane G protein Gi2 and Gi3 are involved in LPA-elicited anti-apoptotic effects through activation of ERK1/2- and PI3 K-pathways. Additionally, H2O2 increases levels of type II of light chain 3B (LC3B II), an autophagy marker, and H2O2-induced autophagy thus protected BMSCs from apoptosis. LPA further increases the expression of LC3B II in the presence of H2O2. In contrast, autophagy flux inhibitor bafilomycin A1 has no effect on LPA's protection of BMSC from H2O2-induced apoptosis. Taken together, our data suggest that LPA rescues H2O2-induced apoptosis mainly by interacting with Gi-coupled LPA3, resulting activation of the ERK1/2- and PI3 K/AKT-pathways and inhibition caspase-3 cleavage, and LPA protection of BMSCs against the apoptosis is independent of it induced autophagy.
梗死心脏中活性氧的增加显著降低了供体间充质干细胞的存活率，从而削弱了对心肌梗死的治疗效果。在我们之前的研究中，我们证明溶血磷脂酸（LPA）可保护骨髓间充质干细胞（BMSCs）免受缺氧和血清剥夺诱导的细胞凋亡。然而，LPA是否能保护BMSCs免受过氧化氢（H2O2）诱导的细胞凋亡尚未得到研究。在本研究中，我们报告H2O2可诱导大鼠BMSC凋亡，而LPA预处理可有效保护BMSCs免受H2O2诱导的凋亡。LPA对BMSC凋亡的保护作用主要通过LPA3受体介导。此外，我们发现膜G蛋白Gi2和Gi3通过激活ERK1/2和PI3K信号通路参与LPA引发的抗凋亡作用。此外，H2O2增加了自噬标志物轻链3B（LC3B II）II型的水平，H2O2诱导的自噬从而保护BMSCs免于凋亡。在H2O2存在的情况下，LPA进一步增加了LC3B II的表达。相比之下，自噬流抑制剂巴弗洛霉素A1对LPA保护BMSC免受H2O2诱导的凋亡没有影响。综上所述，我们的数据表明，LPA主要通过与Gi偶联的LPA3相互作用来挽救H2O2诱导的凋亡，从而激活ERK1/2和PI3K/AKT信号通路并抑制半胱天冬酶-3的切割，并且LPA对BMSCs的抗凋亡保护作用与其诱导的自噬无关。
