ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells.
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.
Baylor Research Institute, Dallas, TX, USA.
Shuyuan
S
Chen
the University of Texas Southwestern Medical Center at Dallas, Medical School, Dallas, TX, , USA.
Jiaxi
J
Chen
Baylor Research Institute, Dallas, TX, USA.
Xing-Li
XL
Meng
Baylor Research Institute, Dallas, TX, USA.
Jin-Song
JS
Shen
Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, China.
Jing
J
Huang
Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, China.
Pintong
P
Huang
Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, China.
Zhaoxia
Z
Pu
Baylor Research Institute, Dallas, TX, USA.
Nathan H
NH
McNeill
Baylor Research Institute, Dallas, TX, USA.|Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA.
Paul A
PA
Grayburn
D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D066126:Cardiotoxicity; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004317:Doxorubicin; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D045423:Microbubbles; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D036361:Peptide Hormones / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000378:metabolism; D020127:Recovery of Function; D012038:Regeneration; D055153:Stem Cell Niche; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014465:Ultrasonics; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
C576683:ANGPTL8 protein, human; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D060850:LIM-Homeodomain Proteins; D036361:Peptide Hormones; C491380:Pirb protein, rat; D011971:Receptors, Immunologic; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D004317:Doxorubicin
Adriamycin cardiomyopathy; Angiopoietin-like protein 8; Paired immunoglobulin like-receptor B (PirB); Progenitor cells; Ultrasound targeted microbubble destruction (UTMD)