ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells.
ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells.
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DOI：
10.18632/oncotarget.13061
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发表时间：
2016-12-06
期刊：
影响因子：
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通讯作者：
Grayburn PA
中科院分区：
文献类型：
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作者：
Chen S;Chen J;Meng XL;Shen JS;Huang J;Huang P;Pu Z;McNeill NH;Grayburn PA
阿霉素心肌病是一种致命的疾病。当充血性心力衰竭发生时，死亡率约为每年50%。已知angptl在脂质代谢、炎症、癌细胞侵袭、造血干细胞活性和糖尿病等方面具有多种功能。我们假设ANGPTL8能够通过刺激成人心脏祖细胞启动心肌再生来维持心脏功能。我们采用UTMD将携带人ANGPTL8基因的转座子质粒传递到阿霉素心肌病大鼠肝脏。ANGPTL8基因经肝传递后，在大鼠肝细胞和血液中发现转基因人ANGPTL8过表达。UTMD- ANGPTL8基因治疗恢复左室质量、分数缩短指数和左室后壁直径接近正常。我们的结果还显示ANGPTL8逆转已建立的ADM心肌病。这与心外膜中is -1阳性心脏祖细胞的激活有关。时间过程实验表明，is -1心肌祖细胞增殖并在心外膜层形成生态位，然后迁移到心外膜亚层。观察到阿霉素心肌病逆转时心肌再生与ANGPTL8刺激心肌细胞或祖细胞细胞膜上PirB表达上调有关。
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.