title: Direct AT₂ receptor stimulation is athero-protective and stabilizes plaque in apolipoprotein E-deficient mice.
abstract: BACKGROUND
  The angiotensin II type 2 receptor (AT₂R) has been suggested to have an athero-protective role, however no studies have investigated the effect of direct stimulation of this receptor in atherosclerosis. Thus this study aimed to determine the effect of direct AT₂R stimulation in setting of atherosclerosis, using the known AT₂R agonist, CGP42112.
  
  
  RESULTS
  Apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high fat (21%) diet for 16 weeks, with subcutaneous infusions of CGP42112 (1, 5 or 10 μg/kg/min) administered via osmotic mini-pumps in the final 4 weeks. CGP42112 treatment at all doses significantly improved endothelial function (p<0.001) when compared to acetylcholine mediated-vasorelaxation in aorta taken from vehicle-treated ApoE(-/-) mice. In aortic segments adjacent to those used for vascular reactivity studies, CGP42112 treatment at all doses concomitantly increased eNOS immunoreactivity and protein levels whilst superoxide (O2(-)) production was significantly (p<0.01) decreased compared to levels measured in aorta from vehicle-treated ApoE(-/-) mice. Moreover, CGP42112 (1 μg/kg/min) treatment significantly attenuated (p<0.05) atherosclerotic lesion progression (assessed as both lipid deposits and luminal encroachment in thoracic aorta and aortic arch) and significantly increased plaque stability in the brachiocephalic artery, a region normally prone to rupture. Both the vaso- and athero-protective effects of CGP42112 (1 μg/kg/min) were reversed with co-infusion of the AT2R antagonist, PD123319, but not the MasR antagonist, A779.
  
  
  CONCLUSIONS
  For the first time we have shown that direct stimulation of the AT₂R improves endothelial function, reduces atherosclerotic lesion progression and mediates plaque stability with these effects at least partly due to restoration of nitric oxide bioavailability.
authors.affiliation: Department of Pharmacology, Monash University, Victoria 3800, Australia.
authors.forename: Sonja Tesanovic
authors.initials: ST
authors.lastname: Kljajic
authors.forename: Robert E
authors.initials: RE
authors.lastname: Widdop
authors.forename: Antony
authors.initials: A
authors.lastname: Vinh
authors.forename: Iresha
authors.initials: I
authors.lastname: Welungoda
authors.forename: Sanja
authors.initials: S
authors.lastname: Bosnyak
authors.forename: Emma S
authors.initials: ES
authors.lastname: Jones
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Gaspari
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002316:Cardiotonic Agents; D009842:Oligopeptides; D044139:Receptor, Angiotensin, Type 2; C060894:CGP 42112A
keywords: AT(2) receptor; Atherosclerosis; CGP42112; Endothelial dysfunction; Plaque rupture