Over-expression of angiotensin II type 2 receptor (agtr2) decreases collagen accumulation in atherosclerotic plaque.
Angiotensin (Ang) II, via type 1 receptor activation, exerts a significant role in atherogenesis and collagen synthesis. To test the hypothesis that Ang II type 2 receptor (AT2R) upregulation delivered with adeno-associated virus type 2 (AAV/AT2R) would inhibit collagen synthesis in atherosclerotic arteries, LDLR knockout mice were injected with AAV/AT2R and fed 4% cholesterol diet for 18 weeks. LDLR knockout mice treated with saline or AAV/Neo exhibited extensive vessel wall collagen accumulation, which was reduced by about 50% with AT2R over-expression. AT2R upregulation completely blocked the alterations in the expression of procollagen-I, osteopontin, fibronectin, CD68, and matrix metalloproteinases (MMP-2 and MMP-9), as well as phosphorylation of p38 and p44/42 MAPKs. Activity of superoxide dismutase was reduced in the LDLR KO mice and it increased with AT2R upregulation. This study demonstrates that AT2R over-expression reduces enhanced collagen accumulation, MMP expression and activity in atherosclerotic regions via inhibition of pro-oxidant signals.
Dandapat
Abhijit
A
Division of Cardiovascular Medicine, Gene Therapy Program, University of Arkansas for Medical Sciences, 4301 West Markham Street Slot 532, Little Rock, AR 72205, USA.
Hu
Chang Ping
CP
Chen
Jiawei
J
Liu
Yong
Y
Khan
Junaid A
JA
Remeo
Francesco
F
Carey
Robert M
RM
Hermonat
Paul L
PL
Mehta
Jawahar L
JL
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D003094:Collagen / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D005353:Fibronectins; D016877:Oxidants; D044139:Receptor, Angiotensin, Type 2; D053495:Osteopontin; D003094:Collagen; D020782:Matrix Metalloproteinases