Department of Cardiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
Acta Biochim Biophys Sin (Shanghai). 2018 Nov 1;50(11):1121-1130. doi: 10.1093/abbs/gmy118.
Apoptosis is involved in the death of cardiac progenitor cells (CPCs) after myocardial infarction (MI) in the heart. The loss of CPCs results in infarct scar and further deterioration of the heart function. Though stem cell-based therapy provides an effective approach for heart function recovery after MI, the retention of CPCs in the infarcted area of the heart is the main barrier that limits its promising therapy. Therefore, the underlying mechanisms of CPC apoptosis in hypoxia are important for the development of new therapeutic targets for MI patients. In this work, we found that the expression of high-mobility group box 1(HMGB1) was upregulated in CPCs under hypoxia conditions. Further study demonstrated that HMGB1 was regulated by DNA methyltransferases 1 (DNMT1) via changing the methylation state of CpGs in the promoter of HMGB1 in CPCs during hypoxia process. Additionally, mitogen-activated protein kinase (MAPK) signaling pathway was found to be involved in regulating DNMT1/HMGB1-mediated CPC apoptosis in hypoxia process. In conclusion, our findings demonstrate a novel regulatory mechanism for CPC apoptosis and proliferation under hypoxia conditions, which may provide a new therapeutic approach for MI patients.
细胞凋亡参与心肌梗死后心脏中的心肌祖细胞（CPCs）的死亡。CPCs 的丧失导致梗死瘢痕和心脏功能的进一步恶化。尽管基于干细胞的治疗为心肌梗死后的心脏功能恢复提供了一种有效方法，但 CPCs 在梗死区的保留是限制其有前途的治疗方法的主要障碍。因此，缺氧条件下 CPC 凋亡的潜在机制对于开发新的 MI 患者治疗靶点非常重要。在这项工作中，我们发现高迁移率族蛋白 B1（HMGB1）在缺氧条件下 CPC 中的表达上调。进一步的研究表明，HMGB1 是通过改变 HMGB1 启动子中 CpGs 的甲基化状态由 DNA 甲基转移酶 1（DNMT1）在缺氧过程中在 CPC 中调节的。此外，发现丝裂原活化蛋白激酶（MAPK）信号通路参与调节缺氧过程中 DNMT1/HMGB1 介导的 CPC 凋亡。总之，我们的研究结果表明，缺氧条件下 CPC 凋亡和增殖存在一种新的调控机制，可为 MI 患者提供一种新的治疗方法。
