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(Hypertension. 2008;51:1339.)
© 2008 American Heart Association, Inc.

Original Articles

Angiotensin II Type 2 Receptor Deletion Enhances Vascular Senescence by Methyl Methanesulfonate Sensitive 2 Inhibition

Li-Juan Min; Masaki Mogi; Jun Iwanami; Jian-Mei Li; Akiko Sakata; Teppei Fujita; Kana Tsukuda; Masaru Iwai; Masatsugu Horiuchi

From the Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Ehime, Japan.

Correspondence to Masatsugu Horiuchi, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

Vascular senescence is closely associated with age-related vascular disorders and is enhanced by angiotensin (Ang) II type 1 receptor stimulation. However, the role of Ang II type 2 receptor activation in vascular senescence is still an enigma. Ang II stimulation significantly increased senescence-associated β-galactosidase activity and the level of 8-hydroxy-2'-deoxyguanosine, with enhancement of oxidative stress and expression of Ki-ras2A, p53, and p21 in vascular smooth muscle cells (VSMCs) from wild-type (Agtr2⁺) mice, whereas these effects of Ang II were enhanced in VSMCs from Ang II type 2 receptor null (Agtr2^–) mice. Administration of an Ang II type 1 receptor blocker, valsartan, attenuated these parameters, with less effect in Agtr2^– VSMCs. Ang II stimulation increased methyl methanesulfonate sensitive 2 (MMS2) expression in Agtr2⁺ VSMCs but not in Agtr2^– VSMCs. MMS2 small-interfering RNA treatment enhanced Ang II–induced senescence-associated β-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level with no significant changes in oxidative stress markers and the expression of Ki-ras2A, p53, and p21. Moreover, exposure of Agtr2⁺ VSMCs to hydrogen peroxide and ultraviolet irradiation induced marked increases in senescence-associated β-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level, which were further enhanced in Agtr2^– and MMS2 small-interfering RNA–treated Agtr2⁺ VSMCs. Agtr2⁺ mice exposed to x-ray irradiation showed increases in senescence-associated β-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level in the aorta, which were further exaggerated in the aorta of Agtr2^– mice with a lower MMS2 level. These findings suggest that Ang II type 2 receptor signaling attenuates DNA damage and consequent vascular senescence at least in part through MMS2 transactivation and propose the beneficial effects of Ang II type 2 receptor stimulation with Ang II type 1 receptor blockers in age-related vascular disorders.

Key Words: angiotensin II type 2 receptor • vascular cell • senescence • methyl methanesulfonate sensitive 2 • DNA damage