Over-expression of angiotensin II type 2 receptor (agtr2) reduces atherogenesis and modulates LOX-1, endothelial nitric oxide synthase and heme-oxygenase-1 expression.
Atherogenesis is associated with inflammation and oxidative stress. Activation of renin-angiotensin system with generation of angiotensin II and type 1 receptor (AT1R) stimulation has been amply reported in atherosclerosis. Since angiotensin II type 2 receptor (AT2R) activity is purported to oppose the effects of AT1R, we hypothesized that AT2R (agtr2) over-expression would inhibit atherogenesis. We prepared recombinant adeno-associated virus type-2 (AAV) carrying AT2R cDNA (AAV/AT2R), and homozygous LDLR-deficient (KO) mice were given AAV/AT2R, AAV/Neo or saline. All mice were placed on a high cholesterol diet. After 18 weeks, AT2R was found to be over-expressed systemically in AAV/AT2R-treated mice. Atherogenesis in aorta was reduced in the AAV/AT2R group by approximately 50% compared to other LDLR KO mice groups. Expression of NADPH oxidase, nitrotyrosine and NF-kappaB was increased in aortic tissues of the LDLR KO mice given saline or AAV/Neo, but not in mice with AT2R upregulation. Expression of endothelial nitric oxide synthase (eNOS) and heme-oxygenase-1 (HO-1) was decreased and that of the lectin-like oxidized-LDL receptor (LOX-1) increased in the LDLR KO mice, but not in the mice with AT2R over-expression. Further, Akt-1 phosphorylation was reduced in the LDLR KO mice, but not in the mice with AT2R over-expression. Thus, AT2R upregulation can reduce atherogenesis, possibly by modulating oxidative stress and the pro-inflammatory cascade, mediated via Akt-1. Over-expression of AT2R may be an important therapeutic approach in atherosclerosis.
Hu
Changping
C
Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR 72205, United States.
Dandapat
Abhijit
A
Chen
Jiawei
J
Liu
Yong
Y
Hermonat
Paul L
PL
Carey
Robert M
RM
Mehta
Jawahar L
JL
D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis* / Q000235:genetics*; D011973:Receptors, LDL / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*
D000809:Angiotensins; C495138:Olr1 protein, mouse; D044139:Receptor, Angiotensin, Type 2; D011973:Receptors, LDL; D051127:Scavenger Receptors, Class E; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1