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(Circulation. 2001;104:2716.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Roles of Angiotensin II Type 2 Receptor Stimulation Associated With Selective Angiotensin II Type 1 Receptor Blockade With Valsartan in the Improvement of Inflammation-Induced Vascular Injury

Lan Wu, MD; Masaru Iwai, MD, PhD; Hironori Nakagami, MD; Zhen Li, MD; Rui Chen, MD; Jun Suzuki, MD; Masahiro Akishita, MD, PhD; Marc de Gasparo, MD, PhD; Masatsugu Horiuchi, MD, PhD

From the Department of Medical Biochemistry, Ehime University School of Medicine, Ehime (L.W., M.I., H.N., Z.L., R.C., J.S., M.H.), and the Department of Geriatric Medicine, Kyorin University School of Medicine, Tokyo (M.A.), Japan; and Novartis Pharma AG, Basel, Switzerland (M.d.G.).

Correspondence to Masatsugu Horiuchi, MD, PhD, Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

Background— To investigate the effect of angiotensin (Ang) II type 1 receptor (AT₁) blocker on vascular remodeling and explore the possibility of the involvement of Ang II type 2 receptor (AT₂) stimulation in this process, we examined the effects of the selective AT₁ blocker valsartan on the vascular injury in wild-type (Agtr2+) and AT₂-null (Agtr2-) mice.

Methods and Results— Neointima formation and the proliferation of vascular smooth muscle cells (VSMCs) induced by cuff placement on the femoral artery were greater in Agtr2- mice than those in Agtr2+ mice. Treatment of mice with valsartan at a dose of 1 mg · kg^-1 · d^-1, which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs, whereas the valsartan was less effective in Agtr2- mice. Moreover, cuff placement increased the expression of monocyte chemoattractant protein-1 (MCP-1); inflammatory cytokines such as tumor necrosis factor (TNF)-, interleukin (IL)-6, and IL-1ß; and infiltration of CD45-positive leukocytes and macrophages in the injured arteries and further enhanced them in Agtr2- mice, suggesting the antagonistic effects of AT₁ and AT₂ for vascular inflammation. Valsartan attenuated the expression of MCP-1, TNF-, IL-6, IL-1ß, and infiltration of leukocytes and macrophages in the injured arteries; however, these effects of valsartan were less prominent in Agtr2- mice.

Conclusions— These results suggest that the stimulation of the AT₂ receptor after AT₁ blockade is important in the improvement of the inflammatory vascular injury.

Key Words: angiotensin • arteries • inflammation • receptors • remodeling