Abstract
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.
Highlights
Adriamycin (ADM) is one of the most widely prescribed and effective cytotoxic drugs used in oncology
Western blotting was employed to detect human ANGPTL8 from liver protein extracts, and the results showed that the human ANGPTL8 signal existed in the liver protein extracts after ultrasound-targeted microbubble destruction (UTMD)-ANGPTL8 gene delivery
Et al [40] reported that cardiac progenitor cells in epicardial layer of adult heart are a resource for www.impactjournals.com/oncotarget myocardial regeneration and they are able to differentiate into cardiac muscle cells, coronary artery muscle cells and vascular endothelial cells
Summary
Adriamycin (ADM) is one of the most widely prescribed and effective cytotoxic drugs used in oncology. Multiple clinical trials of stem cell therapy have been attempted but without clear improvement in cardiac function [16] Part of this problem may be the fact that patients with advanced HF often have lack of blood supply to the heart and extensive scar tissue due to ischemic cardiomyopathy or longstanding non-ischemic cardiomyopathy with extensive fibrosis. Some evidence shows that adult EMCs primarily undergo fibrogenic EMT upon cardiac stress, such as hypertension or infarction, to generate myofibroblast-like cells [21] These cells can contribute to the development of cardiac disease, such as fibrosis, potentially leading to impaired cardiac performance and arrhythmias, including sudden death. It is very crucial to find out the molecular and cellular aspects of these EMCs as well as associated factors, and their implication in EMT and cardiac fibrosis in order to prevent or treat certain heart diseases
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