Chen Tielong, Zhu Houyong, Wang Yu, Zhao Pengjie, Chen Jingyu, Sun Jing, Zhang Xiudong, Zhu Guangli
Department of Cardiology, Hangzhou Hospital of Traditional Chinese Medicine Hangzhou, China.
Am J Transl Res. 2018 Aug 15;10(8):2555-2566. eCollection 2018.
Therapy for myocardial regeneration using bone marrow stromal cells (BM-MSCs) has been applied to improve the cardiac function of subjects with acute myocardial infarction. However, the study of this therapy has encountered a bottleneck because BM-MSCs are prone to apoptosis in ischemic and anoxic environments. The goal of this study was to investigate the expression of mitogen activated protein kinase (MAPK) (p-38, JNK and ERK) and endoplasmic reticulum stress protein (caspase-12 and CHOP) during BM-MSC apoptosis. In a BM-MSC model of hypoxia and serum deprivation (H/SD), we observed the morphology and apoptotic rate of BM-MSCs for 24 h and found that the nuclear shrinkage and apoptosis rate increased gradually and reached a maximum apoptosis rate at the 6 h time point. Then, with the prolongation of the hypoxia time, the number of nuclear shrinkage cells and the apoptosis rate gradually decreased. The expression levels of p-38, JNK, ERK, procaspase-12, caspase-12 and CHOP increased at each H/SD time point. In addition, compared with the H/SD 6 h group, the nuclear shrinkage and apoptosis rate were decreased in the SB202190 and SP600125 groups but increased in the PD98059 group. Further, the expression of caspase-12 in the SB202190 group decreased, while the expression of procaspase-12 increased, compared with the H/SD 6 h group. Overall, our findings suggested that p-38, JNK, CHOP and caspase-12 play important roles in promoting the apoptosis of BM-MSCs, while ERK is contrary to other signals. Moreover, the apoptosis of BM-MSCs was induced by H/SD via the p-38-caspase-12 signaling pathway.
使用骨髓基质细胞（BM-MSCs）进行心肌再生治疗已被应用于改善急性心肌梗死患者的心脏功能。然而，由于BM-MSCs在缺血缺氧环境中易发生凋亡，该疗法的研究遇到了瓶颈。本研究的目的是调查丝裂原活化蛋白激酶（MAPK）（p-38、JNK和ERK）和内质网应激蛋白（caspase-12和CHOP）在BM-MSC凋亡过程中的表达情况。在缺氧和血清剥夺（H/SD）的BM-MSC模型中，我们观察了BM-MSCs 24小时的形态和凋亡率，发现核固缩和凋亡率逐渐增加，并在6小时时间点达到最大凋亡率。然后，随着缺氧时间的延长，核固缩细胞数量和凋亡率逐渐下降。在每个H/SD时间点，p-38、JNK、ERK、procaspase-12、caspase-12和CHOP的表达水平均升高。此外，与H/SD 6小时组相比，SB202190和SP600125组的核固缩和凋亡率降低，而PD98059组则升高。进一步地，与H/SD 6小时组相比，SB202190组中caspase-12的表达降低，而procaspase-12的表达升高。总体而言，我们的研究结果表明，p-38、JNK、CHOP和caspase-12在促进BM-MSCs凋亡中起重要作用，而ERK与其他信号相反。此外，H/SD通过p-38-caspase-12信号通路诱导BM-MSCs凋亡。
