Zhang Ling X, DeNicola Megan, Qin Xin, Du Jianfeng, Ma Julio, Tina Zhao Yu, Zhuang Shougang, Liu Paul Y, Wei Lei, Qin Gangjian, Tang Yaoliang, Zhao Ting C
Department of Medicine, Rhode Island Hospital, Brown Medical School, Brown University, Providence, Rhode Island;
Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, Rhode Island;
Am J Physiol Cell Physiol. 2014 Aug 15;307(4):C358-72. doi: 10.1152/ajpcell.00187.2013. Epub 2014 Jun 18.
We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit(+) CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit(+) CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit(+) CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit(+) CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit(+) CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit(+) CSCs compared with MI hearts engrafted with control siRNA-treated c-kit(+) CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFP-infected c-kit(+) CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit(+) CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit(+) CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit(+) CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.
我们最近发现，体内抑制组蛋白去乙酰化酶（HDAC）可刺激梗死心脏的内源性心肌再生（Zhang L等人，《药理学与实验治疗学杂志》341: 285 - 293, 2012）。此外，我们的观察表明，HDAC抑制促进心脏发生，这与HDAC4减少有关。然而，HDAC4的特异性抑制是否调节心脏干细胞（CSCs）以促进心肌修复并维持心脏功能仍不清楚。从成年小鼠心脏中分离出c-kit(+) CSCs，并用HDAC4 siRNA转染以敲低c-kit(+) CSCs的HDAC4。HDAC4 siRNA的转染导致c-kit(+) CSCs中HDAC4 mRNA和蛋白质显著减少。制造小鼠心肌梗死（MI）以评估当将细胞引入MI心脏时，c-kit(+) CSCs中HDAC4抑制对体内心肌再生的影响。将经HDAC4 siRNA处理的c-kit(+) CSCs移植到MI心脏中可改善心室功能，减轻心室重塑，并促进CSC衍生的再生和新血管形成。此外，与移植了对照siRNA处理的c-kit(+) CSCs的MI心脏相比，接受经HDAC4 siRNA处理的c-kit(+) CSCs的MI心脏中Ki67和BrdU阳性增殖心肌细胞增加。另外，与移植了对照腺病毒GFP感染的c-kit(+) CSCs的MI心脏相比，接受腺病毒HDAC4感染的c-kit(+) CSCs的MI心脏表现出心脏功能恢复减弱、CSC衍生的再生和新血管形成减少，同时伴有不良的心室重塑以及Ki67和BrdU阳性增殖心肌细胞减少。HDAC4抑制在体外促进c-kit(+) CSCs向心脏谱系分化，而HDAC4过表达减弱c-kit(+) CSC衍生的心脏发生。我们的结果表明，HDAC4抑制促进CSC衍生的心脏再生并改善心脏功能的恢复。
