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

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Abstract
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.