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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

	Abstract

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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

	Introduction

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Vascular senescence plays an important role in age-related vascular disorders.¹ Angiotensin (Ang) II type 1 (AT₁) receptor stimulation has recently been suggested to provoke vascular cell senescence.² Treatment with AT₁ receptor blockers (ARBs) showed protective effects on age-associated vascular diseases.³ Moreover, some articles and our study indicated that oxidative stress, Ki-ras2A (a member of the oncoprotein Ras family) and its downstream target (cell cycle transcriptional activator), p53/cyclin-dependent kinase inhibitor, and p21 pathway are involved in the senescence-promoting effect of the AT₁ receptor.^2,4,5

In contrast, the roles of activation of the Ang II type 2 (AT₂) receptor in vascular senescence are totally unknown. AT₂ receptor expression is reported to be upregulated in cardiac senescence,⁶ and AT₂ receptor stimulation is believed to be oppose AT₁ receptor-mediated signaling and functions.⁷ Moreover, AT₂ receptor stimulation has a unique mechanism in addition to a negative interaction with AT₁ receptor signaling.^8–10 Therefore, it is possible that AT₂ receptor activation could prevent vascular senescence via both inhibition of AT₁ receptor-mediated signaling and its own signaling mechanism. Recently, many genetic studies supported the important role of DNA repair in the protection of damaged DNA and the prevention of cellular senescence.¹¹ Methyl methanesulfonate sensitive 2 (MMS2), a family of ubiquitin-conjugating enzyme variants, could act as a key factor for DNA repair.¹² Moreover, we demonstrated previously that AT₂ receptor stimulation induces MMS2 expression, resulting in DNA repair and neural differentiation.^9,13 These findings led to a hypothesis that AT₂ receptor signaling could prevent vascular senescence through 2 mechanisms: an MMS2-mediated protection system for DNA damage and counteracting the AT₁ receptor–mediated signaling pathway.

	Methods

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This study was performed in accordance with the National Institutes of Health guidelines for the use of male wild-type (Agtr2⁺) mice (C57BL/6J; Clea Japan, Inc, Osaka, Japan) and AT₂ receptor null (Agtr2^–) mice (based on the C57BL/6J strain bred in our laboratory). Vascular smooth muscle cells (VSMCs) were isolated from the thoracic aorta of Agtr2⁺ mice and Agtr2^– mice by the explant method. Ang II or other reagents were administrated to VSMCs as described previously.⁴ VSMCs were subjected to repeated 250 mJ/cm² UV irradiation and 2 hours of 600 µmol/L of hydrogen peroxide (H₂O₂) exposure. The irradiated mouse model was performed by 10 Gy of total-body x-ray irradiation before and after valsartan administration. Senescence-associated β-galactosidase (SA-β-gal) activity was measured using a Senescence Detection kit. Immunoblot analysis and RNA interference of MMS2 were performed as described previously.⁴ Activity of nicotinamide-adenine dinucleotide phosphate oxidase in VSMCs was measured by a luminescence assay, and superoxide generation was determined by lucigenin chemiluminescence. Quantification of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a DNA damage marker, was performed by an ELISA. An expanded Methods section is available in the data supplement (available online at http://hyper.ahajournals.org).

	Results

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Deletion of AT₂ Receptor Signaling Enhanced Vascular Senescence and DNA Damage
Ang II (10^–7 mol/L) stimulation and 10-Gy x-ray irradiation induced a significant increase in SA-β-gal activity in VSMCs and in the aorta prepared from Agtr2⁺ mice, respectively, whereas this effect of Ang II or x-ray irradiation was exaggerated in VSMCs or in the aorta prepared from Agtr2^– mice (Figure 1A and 1B and Figure S1A). Moreover, 5 days of the addition of valsartan (10^–5 mol/L), a selective AT₁ receptor blocker, after 5 days of Ang II treatment decreased Ang II–induced SA-β-gal activity in Agtr2⁺ VSMCs, whereas this inhibitory effect of valsartan was weaker in Agtr2^– VSMCs. PD123319 (10^–5 mol/L), a specific AT₂ receptor blocker, treatment for 5 days increased Ang II–induced SA-β-gal activity in Agtr2⁺ VSMCs to near the amount of Agtr2^– VSMCs (Figure 1A). Similarly, administration of valsartan (3 mg/kg per day) to Agtr2⁺ mice decreased x-ray irradiation–induced SA-β-gal activity in the aorta, and this inhibitory effect of valsartan was weaker in Agtr2^– mice (Figure 1B). These results suggest that deletion of AT₂ receptor signaling could enhance vascular senescence.

View larger version (25K): [in this window] [in a new window]   Figure 1. SA-β-gal activity by Ang II stimulation in VSMCs (A) and in the aorta of irradiated mice (B). n=4 for each. Ang II is 10–7 mol/L. Val indicates valsartan (10–5 mol/L) and 3 mg/kg per day. PD123319 is 10–5 mol/L. *P<0.05 vs control in VSMCs or in aorta of Agtr2+ mice. #P<0.01 vs Ang II 10 days or irradiation (+) in Agtr2+ or Agtr2– mice. P<0.01 vs 3, 5, and 10 days of stimulation of Ang II or irradiation (+) in Agtr2+ mice.

8-OHdG level, which is a biomarker of oxidative DNA damage, was similar to SA-β-gal activity (Figure S1B and S1C). We examined Ang II receptor expression and observed that AT₁ receptor expression in VSMCs and in the aorta of Agtr2⁺ mice was not changed by Ang II stimulation (Figure S1D) and x-ray irradiation (data not shown), respectively, whereas AT₂ receptor expression was increased by Ang II stimulation or x-ray irradiation and was further enhanced by valsartan treatment.

Deletion of AT₂ Receptor Signaling Increased Oxidative Stress and the Ki-ras2A-p53-p21 Pathway
We examined the inhibitory effect of AT₂ receptor signaling on AT₁ receptor–mediated oxidative stress and the Ki-ras2A/p53/p21 pathway. Ang II–induced superoxide production and nicotinamide-adenine dinucleotide phosphate oxidase activity in VSMCs (Figure 2A and Figure S2) and x-ray irradiation–induced expression of p47^phox and Rac-1 in the aorta (data not shown) were exaggerated in Agtr2^– mice, respectively. Ang II stimulation markedly increased Ki-ras2A expression time dependently in Agtr2⁺ VSMCs, as we reported previously in rat VSMCs,⁴ and these effects of Ang II were enhanced in Agtr2^– VSMCs (Figure 2B). X-ray irradiation also caused an increase in Ki-ras2A expression in the aorta of Agtr2⁺ mice, which was further enhanced in Agtr2^– mice (Figure 2C). Ang II stimulation also remarkably increased p53 and p21 expression time dependently in Agtr2^– VSMCs more than in Agtr2⁺ VSMCs (Figure 2D). Moreover, the inhibitory effects of valsartan on these oxidative stress markers, Ki-ras2A, p53, and p21 expression in VSMCs or in the aorta were weaker in Agtr2^– mice than in Agtr2⁺ mice (Figure 2A through 2D).

View larger version (30K): [in this window] [in a new window]   Figure 2. Superoxide anion production (A) in VSMCs. Representative photographs are fluorescent-stained VSMCs after 10 days of Ang II stimulation at x20 magnification. Ki-ras2A expression in VSMCs (B) and in the aorta of irradiated mice (C). D, p53 and p21 expression in VSMCs. n=4 for each. *P<0.05 vs control in VSMCs or in aorta of Agtr2+ mice. #P<0.01 vs Ang II for 10 days or irradiation (+) in Agtr2+ or Agtr2– mice. P<0.01 vs 3, 5, and 10 days of stimulation of Ang II or irradiation (+) in Agtr2+ mice.

Inhibition of AT₂ Receptor–Mediated MMS2 Associated With Enhancement of Vascular Senescence and DNA Damage
Ang II stimulation and x-ray irradiation significantly enhanced MMS2 expression in VSMCs and in the aorta of Agtr2⁺ mice, respectively; the addition of valsartan further increased, and treatment with PD123319 attenuated this Ang II or the irradiation effect (Figure S3A and S3B). In contrast, an Ang II–mediated increase in MMS2 expression was not observed in Agtr2^– VSMCs (Figure S3A), and x-ray irradiation–induced MMS2 expression in the aorta was attenuated in Agtr2^– mice (Figure S3B). We chose H₂O₂ or UV irradiation as DNA damage and senescence-inducing factors to further explore the role of MMS2 and observed that the MMS2 level was markedly increased in Agtr2⁺ VSMCs after exposure to H₂O₂ (600 µmol/L) or UV irradiation (250 mJ/cm²), whereas this effect of H₂O₂ or UV irradiation was attenuated in Agtr2^– VSMCs (Figure S3C).

We used the RNA interference method to investigate the effect of MMS2 on SA-β-gal activity and the 8-OHdG level. Under treatment with MMS2 small-interfering RNA (siRNA), the stimulatory effects of Ang II on SA-β-gal activity and 8-OHdG level in Agtr2⁺ VSMCs after 5 days of Ang II treatment were significantly increased compared with those under control-siRNA treatment (Figures 3A and S3D). SA-β-gal activity and the 8-OHdG level were also significantly increased in control-siRNA–treated Agtr2⁺ VSMCs after exposure to H₂O₂ or UV irradiation, and they were further enhanced in control-siRNA–treated Agtr2^– and MMS2-siRNA–treated Agtr2⁺ VSMCs. Moreover, SA-β-gal activity and 8-OHdG level induced by H₂O₂ or UV irradiation were higher in MMS2-siRNA–treated Agtr2^– VSMCs than in control-siRNA–treated Agtr2^– and MMS2-siRNA–treated Agtr2⁺ VSMCs (Figures 3B and S3E).

View larger version (29K): [in this window] [in a new window]   Figure 3. Effects of MMS2-siRNA on Ang II- (A) and H2O2- or UV irradiation–induced (B) senescence in VSMCs. n=4 for each. *P<0.05 vs control in control-siRNA–treated Agtr2+ VSMCs. P<0.01 vs H2O2 or UV irradiation (+) in Agtr2+ VSMCs and Ang II, H2O2, or UV irradiation (+) in control-siRNA–treated Agtr2+ VSMCs. #P<0.01 vs H2O2 or UV irradiation (+) in MMS2-siRNA–treated Agtr2– VSMCs.

Effect of MMS2 on Oxidative Stress and the Ki-ras2A-p53-p21 Pathway
Finally, we examined the association of MMS2 with oxidative stress and the Ki-ras2A-p53-p21 cascade and observed that MMS2-siRNA treatment did not significantly influence the Ang II–induced superoxide production; nicotinamide-adenine dinucleotide phosphate oxidase activity; and Ki-ras2A, p53, and p21 expression on day 5 compared with those in control-siRNA–treated Agtr2⁺ VSMCs (Figure 4A through 4C and Figure S4).

View larger version (22K): [in this window] [in a new window]   Figure 4. Effect of MMS2-siRNA on Ang II–induced superoxide anion production (A) in VSMCs. Effect of MMS2-siRNA on Ang II–induced Ki-ras2A (B) and p53 and p21 expression (C). n=4 for each. *P<0.01 vs control in control-siRNA–treated VSMCs. NS indicates no significance.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Vascular senescence mediated by AT₁ receptor stimulation has been highlighted,² and ARBs have been shown to prevent vascular disorders associated with aging.^3,14 It has been reported that AT₁ receptor blockade and stimulation of unbound AT₂ receptors by Ang II could contribute to vasoprotective effects of ARBs, such as inhibition of vascular remodeling and atherosclerosis.^15,16 However, the roles of AT₂ receptor stimulation in vascular senescence are not well investigated, leading us to examine the possibility that AT₂ receptor signaling could prevent vascular senescence and its possible mechanisms. We demonstrated that vascular senescence evaluated by SA-β-gal activity was more exaggerated in Agtr2^– mice than in Agtr2⁺ mice and that treatment with an ARB, valsartan, prevented vascular senescence, whereas this protective effect of valsartan was weaker in Agtr2^– mice in vitro and in vivo. We observed that AT₂ receptor expression was upregulated in senescent vascular cells of Agtr2⁺ mice. These results indicate that AT₂ receptor signaling could play an important role in attenuating vascular senescence.

Oxidative stress and the oncoprotein Ras, which are essential for various signaling pathways, have been shown recently to trigger cellular senescence by regulating the level of the cyclin-dependent kinase inhibitor.^5,17–19 We have demonstrated that AT₁ receptor–mediated oxidative stress enhances the Ki-ras2A-p53-cyclin-dependent kinase inhibitor p21 pathway, resulting in VSMC senescence.⁴ In the present study, we addressed the issue that AT₂ receptor signaling prevented vascular cell senescence possibly because of its inhibitory effect on the AT₁ receptor–mediated signaling pathway. We demonstrated that oxidative stress; Ki-ras2A, p53, and p21 expression induced by Ang II stimulation; and x-ray irradiation were further enhanced in VSMCs and the aorta in Agtr2^– mice compared with those in Agtr2⁺ mice. Therefore, we assumed a possible antagonistic effect of AT₂ receptor signaling on AT₁ receptor–mediated oxidative stress and the Ki-ras2A-p53-p21 signaling pathway could prevent vascular cell senescence. Although the detailed signaling mechanism of the antagonism of the AT₁ receptor by the AT₂ receptor is still poorly understood, AT₂ receptor stimulation is known to activate a variety of phosphatases and to enhance NO production in VSMCs.²⁰ Protein phosphatases could inactivate Ras-mediated signaling, such as mitogen-activated protein kinase, in response to mechanical stress.²¹ Therefore, the direct downstream targets of Ki-ras2A, such as extracellular signal regulated kinase, p38 mitogen-activated protein kinase, or phosphatidylinositol 3-kinase, may also play potential roles in AT₂ receptor–mediated inhibition of vascular senescence.

Accumulation of a variety of DNA damage induced by environmental stress has been identified recently as a major factor in the progression of premature cell senescence.^22,23 DNA repair systems are important in the prevention of cellular senescence induced by damaged DNA,¹¹ and it is suggested that aging of neurons is characterized by a general reduction in DNA repair capacity.²⁴ Therefore, the balance between accumulation of DNA damage and alterations in DNA repair processes could play an essential role in determining the onset and progress of senescence. We chose H₂O₂, UV irradiation, and x-ray irradiation as DNA damage and senescence-inducing factors to examine the possibility that AT₂ receptor signaling inhibits vascular cell senescence at least because of the attenuation of DNA damage. We demonstrated that the increases of 8-OHdG induced by Ang II administration, H₂O₂ exposure, UV irradiation, and x-ray irradiation were greater in VSMCs and the aorta in Agtr2^– mice than in Agtr2⁺ mice. Our findings suggested that AT₂ receptor signaling could prevent accumulation of DNA damage, contributing to the consequent attenuation of vascular senescence. Recently, it was suggested that oxidative DNA damage dependent on telomere shorting might be involved in AT₁ receptor–mediated replicative senescence.²⁵ Therefore, we need to further study the role of AT₂ receptor signaling in telomere shorting.

We explored the mechanism involved in the protection of DNA damage by AT₂ receptor signaling. MMS2, a family of ubiquitin-conjugating enzyme variants, was recently suggested to induce DNA repair on DNA damage via multiple pathways in neuronal development and differentiation.^12,26 We have reported that AT₂ receptor stimulation could enhance MMS2 expression contributing to DNA repair and neural differentiation.^9,13 Therefore, we speculated that MMS2 might be involved in DNA repair and AT₂ receptor–inhibited VSMC senescence. We observed that MMS2 expression was enhanced by Ang II stimulation and x-ray irradiation in VSMCs and in the aorta of Agtr2⁺ mice, respectively, which was further increased by valsartan treatment. However, the Ang II–mediated increase in MMS2 expression was not observed in Agtr2^– VSMCs. Moreover, using MMS2-siRNA, we indicated that deletion of AT₂ receptor signaling inhibits MMS2 expression, resulting in enhancement of DNA damage and vascular senescence by AT₁ receptor stimulation. We also demonstrated the large increases in the MMS2 level in response to H₂O₂ exposure, UV radiation, and x-ray irradiation in Agtr2⁺ mice, but the small increases in Agtr2^– mice, leading us to assume that the increase in MMS2 could be a compensatory mechanism against DNA damage, and AT₂ receptor signaling could be important for the induction of MMS2 expression and protection of DNA damage in multiple conditions, although other possible pathways than AT₂ receptor signaling could directly upregulate MMS2.²⁷

Our recent study pointed out that a unique mechanism of the AT₂ receptor signaling involving MMS2 transactivation prevents neural damage.⁹ Accordingly, in this study, we demonstrated that MMS2-siRNA treatment has no significant effects on Ang II–induced oxidative stress, and also Ki-ras2A, p53, and p21 expression in Agtr2⁺ VSMC, suggesting that the MMS2 cascade may not be involved in the antagonistic effect of the AT₂ receptor against AT₁ receptor–mediated oxidative stress and the Ki-ras2A-p53-p21 pathway. Our findings support the idea that AT₂ receptor–mediated antisenescence signaling is closely related to an MMS2-dependent protection system for DNA damage, such as DNA repair, in addition to antagonizing AT₁ receptor signaling, and that the MMS2 cascade is an unique mechanism of AT₂ receptor signaling. The signaling cascade from AT₂ receptor stimulation to MMS2 activation and the detailed mechanism of MMS2 in mediating DNA repair and consequent inhibition of vascular senescence need to be further investigated.

Perspectives
Collectively, our findings suggest that AT₂ receptor signaling exerts inhibitory effects on vascular senescence through an MMS2-dependent protection system for DNA damage, such as DNA repair, as well as counteracting AT₁ receptor–mediated oxidative stress and the Ki-ras2A-p53-p21 pathway. We also demonstrated that treatment with an ARB, valsartan, attenuated vascular senescence and DNA damage and that the effects of valsartan were less in Agtr2^– mice, suggesting that both AT₂ receptor signaling and AT₁ receptor blockade are necessary for preventing vascular senescence. We, therefore, propose important beneficial pharmacotherapeutic effects of ARBs, by stimulating the AT₂ receptor, in the application of ARBs to age-related vascular disorders.

	Acknowledgments

 
Sources of Funding

This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan (to M.H., M.M., and L-J.M.) and the Suzuken Memorial Foundation and Takeda Science Foundation (to M.M).

Disclosures

None.

Received November 23, 2007; first decision December 5, 2007; accepted February 19, 2008.

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This Article Abstract Full Text (PDF) Data Supplement All Versions of this Article: 51/5/1339    most recent HYPERTENSIONAHA.107.105692v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Min, L.-J. Articles by Horiuchi, M. Search for Related Content PubMed PubMed Citation Articles by Min, L.-J. Articles by Horiuchi, M. Related Collections Remodeling Cardiovascular Pharmacology ACE/Angiotension receptors Cell signalling/signal transduction Other Vascular biology