Vascular angiotensin II type 2 receptor attenuates atherosclerosis via a kinin/NO-dependent mechanism. (June 2015) - Takata, Hiroki
Introduction: The angiotensin II (Ang II) type 1 receptor exerts pro-atherogenic action by augmenting oxidative stress, whereas the Ang II type 2 receptor (AT2 )-mediated effect on atherosclerosis remains controversial. Materials and methods: AT2 transgenic (AT2 -Tg) mice, which overexpress AT2 in their vascular smooth muscle cells, were crossed with apoE-deficient (apoE -/- ) mice to generate AT2 transgenic apoE -/- mice (AT2 -Tg/apoE -/- ). Results: A subpressor dose of Ang II infusion exaggerated atherosclerosis development in apoE -/- mice, which was markedly suppressed in AT2 -Tg/apoE -/- mice. Inhibitors of nitric oxide (NO) synthase (L-NAME) or bradykinin type 2 receptor completely abolished AT2 -mediated anti-atherogenic actions. The vascular cell adhesion molecule-1 expression levels and degree of monocyte/macrophage accumulation in the intima were also considerably reduced in AT2 -Tg/apoE -/- mice; these phenomena were completely reversed by L-NAME treatment. Ang II infusion significantly enhanced the accumulation of dihydroethidium-positive mononuclear cells in the intima and mRNA expression levels of Nox2, a phagocytic cell-type NADPH oxidase subunit in apoE -/- mice, which was completely inhibited in AT2 -Tg/apoE -/- mice. Conclusions: Vascular AT2 stimulation exerts anti-atherogenic actions in an endothelial kinin/NO-dependent manner, and its anti-oxidative effect is likely to be exerted by inhibiting the accumulation of superoxide-producing mononuclear leukocytes.