Chen Shuyuan, Chen Jiaxi, Meng Xing-Li, Shen Jin-Song, Huang Jing, Huang Pintong, Pu Zhaoxia, McNeill Nathan H, Grayburn Paul A
Baylor Research Institute, Dallas, TX, USA.
the University of Texas Southwestern Medical Center at Dallas, Medical School, Dallas, TX, , USA.
Oncotarget. 2016 Dec 6;7(49):80391-80403. doi: 10.18632/oncotarget.13061.
Established adriamycin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50% in a year. It has been known that ANGPTLs has various functions in lipid metabolism, inflammation, cancer cell invasion, hematopoietic stem activity and diabetes. We hypothesized that ANGPTL8 is capable of maintaining heart function by stimulating adult cardiac progenitor cells to initiate myocardial regeneration. We employed UTMD to deliver piggybac transposon plasmids with the human ANGPTL8 gene to the liver of rats with adriamycin cardiomyopathy. After ANGPTL8 gene liver delivery, overexpression of transgenic human ANGPTL8 was found in rat liver cells and blood. UTMD- ANGPTL8 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Our results also showed that ANGPTL8 reversed established ADM cardiomyopathy. This was associated with activation of ISL-1 positive cardiac progenitor cells in the epicardium. A time-course experiment shown that ISL-1 cardiac progenitor cells proliferated and formed a niche in the epicardial layer and then migrated into sub-epicardium. The observed myocardial regeneration accompanying reversal of adriamycin cardiomyopathy was associated with upregulation of PirB expression on the cell membrane of cardiac muscle cells or progenitor cells stimulated by ANGPTL8.
已确诊的阿霉素性心肌病是一种致命疾病。当发生充血性心力衰竭时，一年内的死亡率约为50%。已知血管生成素样蛋白（ANGPTLs）在脂质代谢、炎症、癌细胞侵袭、造血干细胞活性和糖尿病中具有多种功能。我们假设血管生成素样蛋白8（ANGPTL8）能够通过刺激成年心脏祖细胞启动心肌再生来维持心脏功能。我们采用超声介导的微泡破坏技术（UTMD）将携带人ANGPTL8基因的猪尾巴转座子质粒导入阿霉素性心肌病大鼠的肝脏。在进行ANGPTL8基因肝脏递送后，在大鼠肝细胞和血液中发现转基因人ANGPTL8过表达。UTMD-ANGPTL8基因治疗使左心室质量、缩短分数指数和左心室后壁直径恢复到接近正常水平。我们的结果还表明，ANGPTL8可逆转已确诊的阿霉素性心肌病。这与心外膜中ISL-1阳性心脏祖细胞的激活有关。一项时间进程实验表明，ISL-1心脏祖细胞增殖并在心外膜层形成一个小生境，然后迁移到心外膜下。观察到的伴随阿霉素性心肌病逆转的心肌再生与ANGPTL8刺激的心肌细胞或祖细胞膜上PirB表达上调有关。
