Long-term stable expression of human growth hormone by rAAV promotes myocardial protection post-myocardial infarction.
Recombinant adeno-associated virus (rAAV)-based gene therapy represents a promising approach for the treatment of heart diseases. It has been shown that growth hormone (GH) exerts a favorable effect on cardiovascular function in clinical and animal studies. This study explores a chronic stage after myocardial infarction and the potential therapeutic effects of delivering a human GH gene by rAAV following coronary artery ligation in Sprague-Dawley rats. rAAV vectors stably transduced heart muscle for up to 22 weeks after myocardial infarction (MI). Overexpression of GH via rAAV vectors significantly improved not only cardiac function but also LV pathologic remodeling was attenuated post-MI compared to the control rAAV-lacZ injected group. rAAV-mediated expression of GH also resulted in a significant induction of several angiogenic genes such as eNOS, VEGF and bFGF in rat hearts. Immunohistochemistry revealed an increase in capillary density and proliferation of cells and a decrease in the number of TUNEL-positive cardiomyocytes in the rAAV-GH group. Based on these data, we conclude that rAAV-mediated GH delivery can render a long-term transduction in the infarcted heart and improve cardiac function through promoting angiogenesis and proliferation of cells and protecting cardiomyocytes from ischemia-induced apoptosis.
Kusano
Kengo
K
Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St., Boston, MA 02135, USA.
Tsutsumi
Yoshiaki
Y
Dean
Jarrod
J
Gavin
Mary
M
Ma
Hong
H
Silver
Marcy
M
Thorne
Tina
T
Zhu
Yan
Y
Losordo
Douglas W
DW
Aikawa
Ryuichi
R
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D000229:Dependovirus; D015316:Genetic Therapy; D013006:Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
D013006:Growth Hormone