ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells
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Shuyuan Chen1, Jiaxi Chen2, Xing-Li Meng1, Jin-Song Shen1, Jing Huang3, Pintong Huang3, Zhaoxia Pu3, Nathan H. McNeill1, Paul A. Grayburn1,4
1 Baylor Research Institute, Dallas, TX, USA
2 the University of Texas Southwestern Medical Center at Dallas, Medical School, Dallas, TX, , USA
3 Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, China
4 Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA
Paul A. Grayburn, email:
Keywords: Adriamycin cardiomyopathy, Angiopoietin-like protein 8, Ultrasound targeted microbubble destruction (UTMD), Progenitor cells, Paired immunoglobulin like-receptor B (PirB)
Received: September 24, 2016 Accepted: October 07, 2016 Published: November 03, 2016
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.
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