Ma Wenya, He Fang, Ding Fengzhi, Zhang Lai, Huang Qi, Bi Chongwei, Wang Xiuxiu, Hua Bingjie, Yang Fan, Yuan Ye, Han Zhenbo, Jin Mengyu, Liu Tianyi, Yu Ying, Cai Benzhi, Lu Yanjie, Du Zhimin
Department of Pharmacy of The Second Affiliated Hospital, Harbin Medical University (the Heilongjiang Provincial Key Laboratory of Drug Research, Harbin Medical University), Department of Pharmacology (Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Institute of Clinical Pharmacy, Harbin Medical University, Harbin, China.
Cell Physiol Biochem. 2018;47(3):1287-1298. doi: 10.1159/000490224. Epub 2018 Jun 15.
BACKGROUND/AIMS: Melatonin possesses many biological activities such as antioxidant and anti-aging. Cardiac progenitor cells (CPCs) have emerged as a promising therapeutic strategy for myocardial infarction (MI). However, the low survival of transplanted CPCs in infarcted myocardium limits the successful use in treating MI. In the present study, we aimed to investigate if melatonin protects against oxidative stress-induced CPCs damage and enhances its therapeutic efficacy for MI.
TUNEL assay and EdU assay were used to detect the effects of melatonin and miR-98 on H2O2-induced apoptosis and proliferation. MI model was used to evaluate the potential cardioprotective effects of melatonin and miR-98.
Melatonin attenuated H2O2-induced the proliferation reduction and apoptosis of c-kit+ CPCs in vitro, and CPCs which pretreated with melatonin significantly improved the functions of post-infarct hearts compared with CPCs alone in vivo. Melatonin was capable to inhibit the increase of miR-98 level by H2O2 in CPCs. The proliferation reduction and apoptosis of CPCs induced by H2O2 was aggravated by miR-98. In vivo, transplantation of CPCs with miR-98 silencing caused the more significant improvement of cardiac functions in MI than CPCs. MiR-98 targets at the signal transducer and activator of the transcription 3 (STAT3), and thus aggravated H2O2-induced the reduction of Bcl-2 protein.
Pre-treatment with melatonin protects c-kit+ CPCs against oxidative stress-induced damage via downregulation of miR-98 and thereby increasing STAT3, representing a potentially new strategy to improve CPC-based therapy for MI.
背景/目的：褪黑素具有多种生物学活性，如抗氧化和抗衰老。心脏祖细胞（CPCs）已成为心肌梗死（MI）一种有前景的治疗策略。然而，移植的CPCs在梗死心肌中的低存活率限制了其在治疗MI中的成功应用。在本研究中，我们旨在探讨褪黑素是否能保护CPCs免受氧化应激诱导的损伤，并增强其对MI的治疗效果。
采用TUNEL法和EdU法检测褪黑素和miR-98对H2O2诱导的细胞凋亡和增殖的影响。利用MI模型评估褪黑素和miR-98的潜在心脏保护作用。
褪黑素在体外减轻了H2O2诱导的c-kit+CPCs增殖减少和凋亡，与单独移植CPCs相比，体内预先用褪黑素处理的CPCs显著改善了梗死心脏的功能。褪黑素能够抑制H2O2诱导的CPCs中miR-98水平升高。miR-98加剧了H2O2诱导的CPCs增殖减少和凋亡。在体内，移植沉默miR-98的CPCs比移植普通CPCs能更显著地改善MI后的心脏功能。miR-98靶向信号转导和转录激活因子3（STAT3），从而加剧H2O2诱导的Bcl-2蛋白减少。
褪黑素预处理通过下调miR-98并由此增加STAT3来保护c-kit+CPCs免受氧化应激诱导的损伤，这代表了一种潜在的新策略，可改善基于CPCs的MI治疗。
