398 Evidence of a Direct Mas-At2 Receptor Dimerization

Abstract

Objectives AT 2 R defi ciency exacerbates atherosclerotic progression in ApoE (-/-) mice. Because AT 2 Rs are low/undetectable in wild-type (WT) C57BL/6 aortas we hypothesize that ApoE regulates vascular AT 2 Rs. MethodsWe measured AT 2 Rs (using quantitative-immunofl uorescence) in aortic arch vascular smooth muscle (VSMC) and endothelial cell (EC) layers and mean arterial blood pressure (MAP) in anesthetized mice. Nine-week-old ApoE (-/-) and WT mice were fed a low (LC) or high cholesterol (HC) diet for 1 week. Animals were administered vehicle or Ang II (12 g/kg/hr), with or without PD123319 (10 mg/kg/day) (AT 2 R antagonist) for 7 days. ResultsIn LC/ApoE (-/-) vs. WT mice, VSMC and EC AT 2 R was 80-and 26-fold higher (P Ͻ 0.001). HC increased serum cholesterol ~2-fold (P Ͻ 0.001) and decreased VSMC AT 2 R levels 9.5-fold (P Ͻ 0.01) in ApoE (-/-) mice. Low-dose Ang II infusion, which was without effect in LC/WT mice decreased MAP by 15% in LC/ApoE (-/-) (79 Ϯ 2 vs. 67 Ϯ 3 mmHg, vehicle vs. Ang II, respectively; n ϭ 10/gp., P Ͻ 0.01) but not HC/ ApoE (-/-) mice (82 Ϯ 3 vs. 80 Ϯ 2 mmHg vehicle vs. Ang II, respectively; n ϭ 7-11/gp.). A study of vasodilator mechanisms indicated that lowdose Ang II caused a ~6-fold increase in VSMC, but not EC, PPAR-␥ (P Ͻ 0.001) in LC/ApoE (-/-) mice; both VSMC and EC phospho-nitric oxide synthase were not signifi cantly changed. These effects were blocked by PD123319.Methods Male spontaneously hypertensive rats (SHRs) were divided into six groups and treated transiently with three injections of vehicle or AT1 receptor vaccine (0.1 mg) at age 4, 6 and 8 weeks, or continuously with candesartan cilexetil (0.1 mg/kg/day) or hydralazine hydrochloride (5 mg/kg/day), then administered NG-nitro-Larginine methyl ester (L-NAME) from age 18 to 21 weeks to induce renal injury. ResultsVaccination against the AT1 receptor caused a signifi cant increase in AT1 receptor titers, and a sustained decrease in BP. L-NAME

Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison

“…Preliminary data from our group indeed indicate that there exists a physical and functional interaction of these two receptors [64,65]. However, these early observations need confirmation.…”