Inhibitory Effects of AT
            <sub>1</sub>
            Receptor Blocker, Olmesartan, and Estrogen on Atherosclerosis Via Anti-Oxidative Stress

Tsuda, Masahiro; Iwai, Masaru; Li, Jianmei; Li, Huan-Sheng; Min, Li‐Juan; Ide, Akio; Okumura, Midori; Suzuki, Jun; Mogi, Masaki; Suzuki, Hiromichi; Horiuchi, Masatsugu

doi:10.1161/01.hyp.0000157409.88971.fc

Cited by 104 publications

(76 citation statements)

References 43 publications

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“…17,18 Therefore, there is a possibility that progesterone plays some role in the enhancement of vascular remodeling in ovariectomized mice. However, our group has previously reported that increased neointimal formation, DNA synthesis, and atherosclerotic lesions in ovariectomized mice were reversed by treatment with estrogen to the physiologic (female) level, 9,10 suggesting that estrogen contributes to improvements in vascular remodeling over and above the apparent opposite effects of progesterone. The effect of ovariectomy on vascular remodeling was attenuated in Agtr2Ϫ mice, however, suggesting the possibility that estrogen could exert its vascular protective effects at least in part in concert with AT 2 receptor stimulation.…”

Section: Discussionmentioning

confidence: 98%

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Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT ₂ Receptor Expression

et al. 2005

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Abstract-The angiotensin II type 2 (AT 2 ) receptor is upregulated in pathological conditions such as vascular injury and exerts antagonistic effects against AT 1 receptor-mediated actions. We examined the possibility that the sex difference in vascular remodeling is associated with altered AT 2 receptor expression, which is located on the X chromosome. In this study, we examined this possibility by using AT 2 receptor-null (Agtr2Ϫ) mice. Vascular injury was induced by polyethylene cuff placement around the femoral artery of wild-type (Agtr2ϩ) and Agtr2Ϫ mice. In Agtr2ϩ mice, AT 2 receptor expression in the injured artery was enhanced, and this increase was greater in female than in male mice, with no significant difference in AT 1 receptor expression between male and female mice. Increases in neointimal formation, DNA synthesis, expression of monocyte chemoattractant protein-1, production of superoxide anion, and NADPH oxidase activity in the injured artery were attenuated in female compared with male mice. These parameters were augmented in Agtr2Ϫ mice, whereas the sex differences in these parameters were smaller in Agtr2Ϫ than in Agtr2ϩ mice. Treatment with a nonhypotensive dose of the AT 1 receptor blocker valsartan decreased these parameters significantly in Agtr2ϩ mice, and these inhibitory effects of valsartan were greater in female mice. This sex difference in valsartan's inhibitory effect was less marked in Agtr2Ϫ mice. Our results suggest that the sex difference in response to vascular injury could be at least partially attributed to the exaggerated AT 2 receptor expression in the injured vessel in female mice. Key Words: angiotensin II Ⅲ inflammation Ⅲ oxidative stress Ⅲ receptors, angiotensin Ⅲ remodeling R ecent evidence has revealed that actions of the angiotensin (Ang) II receptor subtypes AT 1 and AT 2 are mutually antagonistic. 1,2 The AT 2 receptor is abundantly and widely expressed in fetal tissues, but its expression declines rapidly after birth. 3,4 Interestingly, the AT 2 receptor is reexpressed in certain pathological conditions such as inflammation and vascular injury. 1,2 These findings suggest that the AT 2 receptor plays an important role not only in vasculogenesis but also in vascular remodeling.The effect of AT 1 receptor blockers (ARBs) may not be entirely due to the blockade of the AT 1 receptor. When the AT 1 receptor is blocked, increased Ang II may act on the AT 2 receptor, which could be involved in the effects of the ARB. The AT 2 receptor plays a role in the pathogenesis of cardiovascular and renal diseases. However, the results, though suggestive, are sometimes equivocal. A more extensive knowledge of the AT 2 receptor could therefore contribute to the understanding of the clinical benefits of ARBs. We have previously reported that the AT 2 receptor exerts antiinflammatory and antiproliferative effects by counteracting the AT 1 receptor in the process of neointimal formation after vascular injury in a mouse model of vascular disease induced by polyethylene cuff placement. 5,...

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Section: Discussionmentioning

confidence: 98%

“…Estrogen concentration was measured as previously described 9,10 with an enzyme immunoassay kit (Cayman Chemical Inc). This assay is based on competition between free estradiol and an estradiol tracer for estradiol-specific rabbit antiserum binding sites.…”

Section: Measurement Of Plasma Estrogen Concentrationmentioning

confidence: 99%

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT ₂ Receptor Expression

et al. 2005

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“…This suggests that the activation of RAS may be independent of the abnormality of calcium metabolism. In vasculature, Horiuchi and colleagues 23,24 showed that estrogen antagonized Ang II signaling and Ang II induced atherosclerosis, which suggest that OVX might accelerate Ang II-induced signaling. Of importance, recent reports suggest that estrogen may enhance the ACE inhibition-mediated improvement of vascular remodeling in hypertension in female SHR with OVX through the inhibition of extracellular signal-regulated kinase 1/2.…”

Section: Discussionmentioning

confidence: 99%

Prevention of osteoporosis by angiotensin-converting enzyme inhibitor in spontaneous hypertensive rats

et al. 2009

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A recent analysis of clinical studies suggests that angiotensin-converting enzyme (ACE) inhibitors might reduce bone fractures. In this study, we examined whether an ACE inhibitor might attenuate osteoporosis in a hypertensive rat model. In spontaneous hypertensive rats (SHRs), estrogen deficiency induced by ovariectomy (OVX) resulted in a significant increase in osteoclast activation as assessed by the tartrate-resistant acid phosphatase (TRAP) activity in the tibia, accompanied by a significant decrease in bone density evaluated by dual-energy X-ray absorptiometry and an increase in urinary deoxypyridinoline. Treatment with an ACE inhibitor, imidapril, attenuated OVX-induced decrease in bone density and increase in TRAP activity and urinary deoxypyridinoline. As ACE inhibitors possess the effects of blockade of the renin-angiotensin system (RAS) and activation of the bradykinin-nitric oxide pathway, we examined the contribution of both pathways in an OVX-induced osteoporosis model. Administration of nitro-L-arginine methylester (L-NAME) did not alter TRAP activity, urinary deoxypyridinoline or bone density, whereas the administration of a subpressor dose of angiotensin II accelerated the increase in TRAP activity in the tibia, accompanied by a significant decrease in bone density and an increase in urinary deoxypyridinoline. Thus, ACE inhibitors prevented osteoporosis, probably because of the inhibition of RAS, but not of nitric oxide. Overall, ACE inhibitors attenuated osteoporosis in a hypertensive rat model through the blockade of RAS.

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“…In the present study, we addressed this important point. It is well known that enhanced ROS production accelerates atherosclerosis and mono-therapy with an ARB or a CCB decrease ROS production in animal models (Tsuda et al 2005;Yamamoto et al 2008). The present study further demonstrates that the combination therapy with OLM plus AZL exerts additive anti-atherogenic effects in diabetic ApoE −/− mice, which could explain, at least in part, the beneficial effects of this combination therapy in humans (Kojima et al 2011).…”

Section: Anti-atherogenic Effects Of Olm Plus Azlmentioning

confidence: 99%

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

Noda

Hosoya

Nakajima

et al. 2012

Tohoku J. Exp. Med.

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Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE −/− ) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE −/− mice. Diabetic ApoE −/− mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/ kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE −/− mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.

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Inhibitory Effects of AT ₁ Receptor Blocker, Olmesartan, and Estrogen on Atherosclerosis Via Anti-Oxidative Stress

Cited by 104 publications

References 43 publications

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT ₂ Receptor Expression

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT ₂ Receptor Expression

Prevention of osteoporosis by angiotensin-converting enzyme inhibitor in spontaneous hypertensive rats

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

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Inhibitory Effects of AT 1 Receptor Blocker, Olmesartan, and Estrogen on Atherosclerosis Via Anti-Oxidative Stress

Cited by 104 publications

References 43 publications

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT 2 Receptor Expression

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT 2 Receptor Expression

Prevention of osteoporosis by angiotensin-converting enzyme inhibitor in spontaneous hypertensive rats

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

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Product

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Inhibitory Effects of AT ₁ Receptor Blocker, Olmesartan, and Estrogen on Atherosclerosis Via Anti-Oxidative Stress

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT ₂ Receptor Expression

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT ₂ Receptor Expression