Up-Regulation of Angiotensin II Type 2 Receptor in Rat Thoracic Aorta by Pressure-Overload

Abstract

We have examined whether expression of angiotensin II (Ang II) type 1 (AT 1 ) and/or type 2 (AT 2 ) receptors are changed in thoracic aorta under pressure-overload by abdominal aortic banding in rats and determined whether their changes are accompanied by alteration in contractile response of thoracic aorta to Ang II. AT 2 receptor mRNA levels determined by reverse transcription-polymerase chain reaction or quantitative real-time polymerase chain reaction were increased by about 300% in aortas 4, 7, 14, and 28 days after banding without changes in AT 1 receptor mRNA levels. Contractile response of aortic rings to Ang II was decreased in thoracic aortas 7 days after banding, and AT 2 receptor antagonist PD123319 (1-[[4-(dimethulamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate) (10 Ϫ6 M) increased the Ang II responsiveness in pressure-loaded but not in sham rings. After removal of the endothelium or treatment with N G -nitro-L-arginine methyl ester (L-NAME), no differences were observed in Ang II responsiveness between sham and pressure-loaded rings. Either losartan (1 mg/kg/day i.p.) or candesartan (2 mg/kg/day p.o.) for 7 days after banding not only abolished the up-regulation of AT 2 receptor mRNA in aortas but also recovered their Ang II responsiveness. Basal cGMP levels were 2 times higher in pressureloaded than in sham rings; both levels were not affected by Ang II (10 Ϫ7 M; 5 min), but greatly decreased by L-NAME (10 Ϫ4 M, 30 min). These results suggest that pressure-overload induces the up-regulation of AT 2 receptor expression in aortas via AT 1 receptor and thereby negatively modulates the vasoconstrictor sensitivity to Ang II, probably mediated by the mechanisms independent of the nitric oxide-cGMP system.

Alteration of p66shc is associated with endothelial dysfunction in the abdominal aortic coarctation of rats

“…We used the abdominal aortic coarctation rat model which has shown hypertension in the proximal part and hypotension in the distal part of aortic coarctation within 7 days. The reduced renal perfusion lasts for 2-6 days after coarctation [25], therefore, circulating humoral factors are identical on both sides of the coarctation, the possible causes of the endothelial dysfunction could be due to the change of baromechanical forces or local effects as opposed to systemic humoral effects in the abdominal aortic coarctation models.…”

“…The abdominal aortic coarctation induces hypertension as the activation of reninangiotensin system [14,15,25]. High arterial blood pressure can also induce the activation of the local renin-angiotensin system in the vascular wall, contributing to hypertension-induced oxidative stress [19].…”

Systems Analysis of the Cardiac Myocyte Hypertrophy Signaling Network

“…α1A and α1B receptor subtypes have been shown to colocalize with Gαq and PLCβ1 at the nuclear membrane in adult mouse cardiac myocytes [22]. Moreover, membrane permeable α1AR…”

“…antagonist prazosin blocked phosphorylation of ERK in adult mouse cardiac myocytes while membrane impermeable α1AR antagonist CGP-12177a did not [22]. catecholamines.…”

“…Conversely, pressure overload increased levels of Angiotensin II, catecholamines, and endothelin-1 [22][23][24]. Mice with reduced cardiac PI3K activity showed a reduced hypertrophic response to swimming, but not pressure overload induced hypertrophy [25], while rats with Angiotensin II receptor inhibition showed reduced pressure overload hypertrophy [26], but not exercise induced hypertrophy [27].…”