Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart.
VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China.
Zhengxian
Z
Tao
Bo
B
Chen
Xiao
X
Tan
Yingming
Y
Zhao
Liansheng
L
Wang
Tiebing
T
Zhu
Kejiang
K
Cao
Zhijian
Z
Yang
Yuet Wai
YW
Kan
Hua
H
Su
D042683:Angiopoietin-1 / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000254:growth & development; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D018919:Neovascularization, Physiologic; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000502:physiology
D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A
J Thorac Cardiovasc Surg. 1998 Jan;115(1):168-76; discussion 176-7
9451061
Circulation. 2006 Jul 4;114(1 Suppl):I206-13
16820573
Annu Rev Med. 2008;59:13-28
18186701
Gene Ther. 1998 Jul;5(7):938-45
9813665
Acta Pharmacol Sin. 2006 May;27(5):555-60
16626510
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8801-5
9671759
Circ Res. 2004 Jun 25;94(12):1606-14
15142950
Nat Med. 1995 Oct;1(10):1085-9
7489368
Circulation. 1998 Nov 10;98(19):2081-7
9808608
Blood. 2002 Oct 1;100(7):2487-93
12239160
Int J Cardiol. 2009 Apr 3;133(2):191-7
18295361
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13801-6
11095751
Gene Ther. 2006 Nov;13(22):1564-8
16810195
Nat Med. 2002 Aug;8(8):864-71
12134142
J Am Coll Cardiol. 2000 Apr;35(5):1323-30
10758976
Circ Res. 2001 Feb 2;88(2):167-74
11157668
Gene Ther. 2005 Feb;12(3):196-202
15510173
Circulation. 1994 Nov;90(5 Pt 2):II228-34
7525111
J Biol Chem. 2004 Aug 20;279(34):35858-66
15159393
Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16280-5
15534198
Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15546-51
17032753
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9480-5
12084814
Nat Med. 1996 May;2(5):534-9
8616711
J Am Coll Cardiol. 2003 Oct 1;42(7):1318-33
14522503
Circulation. 2000 Aug 22;102(8):898-901
10952959
Gene Ther. 2006 Nov;13(21):1495-502
16775632
Circ Res. 2006 Aug 18;99(4):381-8
16840722
Circulation. 2002 Jan 29;105(4):539-42
11815441
Circulation. 1998 Feb 24;97(7):645-50
9495299
Circulation. 2000 Feb 1;101(4):454-8
10653839
J Am Coll Cardiol. 2004 Jan 21;43(2):194-9
14736437
Circulation. 1998 Dec 22-29;98(25):2800-4
9860779
Circulation. 1992 Dec;86(6 Suppl):III47-52
1424051
J Clin Invest. 1994 Aug;94(2):623-30
7518840
Cardiovasc Res. 2008 Nov 1;80(2):181-90
18596061