JOURNAL ARTICLE

Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice

Masaru Iwai, Rui Chen, Zhen Li, Tetsuya Shiuchi, Jun Suzuki, Ayumi Ide, Masahiro Tsuda, Midori Okumura, Li-Juan Min, Masaki Mogi, Masatsugu Horiuchi
Circulation 2005 September 13, 112 (11): 1636-43
16145000

BACKGROUND: The role of angiotensin II (Ang II) type 2 (AT2) receptor in atherosclerosis was explored with the use of AT2 receptor/apolipoprotein E (ApoE)-double-knockout (AT2/ApoE-DKO) mice, with a focus on oxidative stress.

METHODS AND RESULTS: After treatment with a high-cholesterol diet (1.25% cholesterol) for 10 weeks, ApoE-knockout (KO) mice developed atherosclerotic lesions in the aorta. In AT2/ApoE-DKO mice receiving a high-cholesterol diet, the atherosclerotic changes were further exaggerated, without significant changes in plasma cholesterol level and blood pressure. In the atherosclerotic lesion, an increase in superoxide production, NADPH oxidase activity, and expression of p47phox was observed. These changes were also greater in AT2/ApoE-DKO mice. An Ang II type 1 (AT1) receptor blocker, valsartan, inhibited atherosclerotic lesion formation, superoxide production, NADPH oxidase activity, and p47phox expression; these inhibitory effects were significantly weaker in AT2/ApoE-KO mice. We further examined the signaling mechanism of the AT2 receptor-mediated antioxidative effect in cultured fetal vascular smooth muscle cells. NADPH oxidase activity and phosphorylation and translocation of p47phox induced by Ang II were inhibited by valsartan but enhanced by an AT2 receptor blocker, PD123319.

CONCLUSIONS: These results suggest that AT2 receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT2 receptor stimulation by unbound Ang II.

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