Angiotensin II type 2 receptor deletion enhances vascular senescence by methyl methanesulfonate sensitive 2 inhibition.
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 beta-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 beta-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 beta-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 beta-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.
Min
Li-Juan
LJ
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Ehime, Japan.
Mogi
Masaki
M
Iwanami
Jun
J
Li
Jian-Mei
JM
Sakata
Akiko
A
Fujita
Teppei
T
Tsukuda
Kana
K
Iwai
Masaru
M
Horiuchi
Masatsugu
M
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology*; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology; D004249:DNA Damage; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism
C528430:Kras protein, rat; D044139:Receptor, Angiotensin, Type 2; D016159:Tumor Suppressor Protein p53; C511778:Ube2v2 protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D016283:Proto-Oncogene Proteins p21(ras)