Research Center for Cardiac Regenerative Medicine, The Ministry of Health, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100037, PR China.
J Cell Biochem. 2010 Nov 1;111(4):811-20. doi: 10.1002/jcb.22731.
Poor viability of transplanted mesenchymal stem cells (MSCs) in the infracted heart has limited their therapeutic efficacy in cardiac repair after myocardial infarction. We previously demonstrated that hypoxia and serum deprivation (hypoxia/SD) induced mitochondria-dependent apoptosis in MSCs, while lysophosphatidic acid (LPA) could almost completely block this apoptotic process. However, the role of endoplasmic reticulum (ER) stress and its upstream signaling events in hypoxia/SD-induced MSC apoptosis remain largely unknown. Here we found that hypoxia/SD-induced MSC apoptosis was associated with ER stress, as shown by the induction of CHOP expression and procaspase-12 cleavage, while the effects were abrogated by LPA treatment, suggesting ER stress is also a target of LPA. Furthermore, hypoxia/SD induced p38 activation, inhibition of which resulted in decreases of apoptotic cells, procaspase-12 cleavage and mitochondrial cytochrome c release that function in parallel in MSC apoptosis. Unexpectedly, p38 inhibition enhanced hypoxia/SD-induced CHOP expression. Interestingly, p38 activation, a common process mediating various biological effects of LPA, was inhibited by LPA in this study, and the regulation of p38 pathway by LPA was dependent on LPA(1/3)/Gi/ERK1/2 pathway-mediated MKP-1 induction but independent of PI3K/Akt pathway. Collectively, our findings indicate that ER stress is a target of LPA to antagonize hypoxia/SD-induced MSC apoptosis, and the modulation of mitochondrial and ER stress-associated apoptotic pathways by LPA is at least partly dependent on LPA(1/3)/Gi/ERK/MKP-1 pathway-mediated p38 inhibition. This study may provide new anti-apoptotic targets for elevating the viability of MSCs for therapeutic potential of cardiac repair.
移植的间充质干细胞（MSCs）在梗死心脏中的活力不佳，限制了它们在心肌梗死后心脏修复中的治疗效果。我们之前的研究表明，缺氧和血清剥夺（hypoxia/SD）诱导 MSCs 中线粒体依赖性凋亡，而溶血磷脂酸（LPA）几乎可以完全阻断这一凋亡过程。然而，内质网（ER）应激及其上游信号事件在缺氧/SD 诱导的 MSC 凋亡中的作用在很大程度上仍不清楚。在这里，我们发现缺氧/SD 诱导的 MSC 凋亡与 ER 应激有关，这表现在 CHOP 表达和 procaspase-12 切割的诱导上，而 LPA 处理则阻断了这一过程，表明 ER 应激也是 LPA 的作用靶点。此外，缺氧/SD 诱导 p38 激活，抑制 p38 可减少凋亡细胞、procaspase-12 切割和线粒体细胞色素 c 释放，这些过程在 MSC 凋亡中协同作用。出乎意料的是，p38 抑制增强了缺氧/SD 诱导的 CHOP 表达。有趣的是，在本研究中，LPA 抑制了 p38 的激活，而 p38 的激活是 LPA 介导的各种生物学效应的共同过程，LPA 对 p38 通路的调节依赖于 LPA(1/3)/Gi/ERK1/2 通路介导的 MKP-1 诱导，而不依赖于 PI3K/Akt 通路。综上所述，我们的研究结果表明，ER 应激是 LPA 拮抗缺氧/SD 诱导的 MSC 凋亡的作用靶点，LPA 对线粒体和 ER 应激相关凋亡途径的调节至少部分依赖于 LPA(1/3)/Gi/ERK/MKP-1 通路介导的 p38 抑制。这项研究可能为提高 MSC 的活力以实现心脏修复的治疗潜力提供新的抗凋亡靶点。
