Blockade of Angiotensin II Receptors Reduces the Expression of Receptors for Advanced Glycation End Products in Human Endothelial Cells

Fujita, Masashi; Okuda, Hiroko; Tsukamoto, Osamu; Asano, Yoshihiro; Y, Hirata; Kim, Jiyoong; Miyatsuka, Takeshi; Takashima, Seiji; Minamino, Tetsuo; Tomoike, Hitonobu; Kitakaze, Masafumi

doi:10.1161/01.atv.0000239569.99126.37

Cited by 31 publications

(25 citation statements)

References 16 publications

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“…In the present study, RAS blockade by temocaprilat and olmesartan, as well as DPI and NAC, markedly attenuated AGEtriggered RAGE expression, suggesting that both agents are capable of attenuating AGE-triggered RAGE activation. These findings are consistent with previous reports 36,42) and support the beneficial effects of ACEI and ARB in diabetic vascular complications.…”

Section: Discussionsupporting

confidence: 93%

Blockade of Renin-Angiotensin System Attenuates Advanced Glycation End Products-Mediated Signaling Pathways

Kamioka

Ishibashi

Sugimoto

et al. 2010

JAT

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Aim: Advanced glycation end products (AGE) and a receptor for AGE (RAGE) play a key role in diabetic vascular complications. Matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. The renin-angiotensin system (RAS) is crucial for NADPH oxidase-dependent redox signaling pathways in the vascular wall. We investigated the effects of RAS blockade on AGE-triggered signaling pathways and its downstream events, including MMP-9 and apoptosis. Methods: We used cultured rabbit aortic smooth muscle cells (SMCs), which were stimulated with AGE in the presence or absence of temocaprilat or olmesartan. Results: Angiotensin converting enzyme (ACE) mRNA levels were increased 4 to 6 hours after adding AGE. AGE induced Rac1 and p47 phox membrane translocation, reactive oxygen species (ROS) generation and NF-B phosphorylation within 15 minutes, and various molecular expressions after 18 hours, which were attenuated by RAS blockade by temocaprilat or olmesartan. AGE-induced RAGE expression, as well as other molecules, including membrane type 1-MMP (MT1-MMP), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), was NADPH oxidase signaling-dependent and blunted by temocaprilat and olmesartan. The parameters of plaque instability, including MMP-9 expression and activity, and apoptosis were up-regulated by AGE, which was markedly attenuated by temocaprilat or olmesartan. Using isolated human monocyte culture, AGE-induced ROS generation and molecular expression were also attenuated by RAS blockade.Conclusion: The present study shows that AGE-triggered NADPH oxidase signaling pathways, including MMP-9 and apoptosis, were attenuated by RAS blockade, which may be an attractive strategy for treating plaque instability in diabetic vascular complications. J Atheroscler Thromb, 2010; 17:590-600.

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Section: Discussionsupporting

confidence: 93%

Blockade of Renin-Angiotensin System Attenuates Advanced Glycation End Products-Mediated Signaling Pathways

Kamioka

Ishibashi

Sugimoto

et al. 2010

JAT

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“…Although such an effect on the AGE/RAGE axis has previously been observed in cell culture experiments [44] and postulated to be important in type 2 diabetic patients for plaque stabilisation [43], this is the first study to demonstrate effects of a statin on the AGE/RAGE pathway in diabetesaccelerated atherosclerosis. Indeed, our study suggests that statins may reduce AGE accumulation and thereby reduce activation of NAD(P)H oxidase, thus linking oxidant stress to altered gene expression via RAGE, as previously suggested in vitro and in gp91phox-deficient mice [45].…”

Section: Discussionmentioning

confidence: 63%

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

et al. 2008

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Aims/hypothesis We evaluated the anti-atherosclerotic effect of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, rosuvastatin, and the angiotensin II receptor blocker (ARB), candesartan, alone and in combination, in the streptozotocin-induced diabetic apolipoprotein Edeficient (Apoe −/− ) mouse. Methods Control and streptozotocin-induced diabetic Apoe −/− mice received rosuvastatin (5 mg kg −1 day −1 ), candesartan (2.5 mg kg −1 day −1 ), dual therapy or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent visual quantification. The abundance of proteins was measured using immunohistochemistry. Results Diabetes was associated with a fourfold increase in total plaque area. Rosuvastatin attenuated plaque area in diabetic mice in the absence of lipid-lowering effects. The anti-atherosclerotic effect of rosuvastatin was comparable to that observed with candesartan. A similar beneficial effect was seen with dual therapy, although it was not superior to monotherapy. Rosuvastatin treatment was associated with attenuated accumulation of AGE and AGE receptor (RAGE) in plaques. Similar beneficial effects on markers of oxidative stress were seen with the ARB and statin. Candesartan was more effective at reducing macrophage accumulation and collagen I abundance in plaques compared with rosuvastatin. The combined effect of candesartan and rosuvastatin was superior in reducing macrophage infiltration, monocyte chemoattractant protein-1 level, vascular AGE accumulation and RAGE abundance in the vascular wall. Furthermore, the combination tended to be more effective in reducing smooth muscle cell infiltration and connective tissue growth factor abundance in plaques. Conclusions/interpretation Rosuvastatin has direct antiatherosclerotic effects in diabetic macrovascular disease. These effects are independent of effects on lipids and comparable to the effects observed with candesartan.

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“…This up-regulation of the AGEs-RAGE axis activates NADPH oxidase with a resultant ROS generation (Wautier et al 2001) and atherosclerosis progression (Schmidt et al 1999). It has been reported that some ARBs (including OLM) (Fujita et al 2006) and nifedipine (a dihydropyridine CCB) reduce RAGE expression (Matsui et al 2009). Furthermore, it was recently reported that the combination therapy with OLM and AZL reduces ROS production via suppression of p22 phox and p47 phox expression and NADPH oxidase activity .…”

mentioning

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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Blockade of Angiotensin II Receptors Reduces the Expression of Receptors for Advanced Glycation End Products in Human Endothelial Cells

Cited by 31 publications

References 16 publications

Blockade of Renin-Angiotensin System Attenuates Advanced Glycation End Products-Mediated Signaling Pathways

Blockade of Renin-Angiotensin System Attenuates Advanced Glycation End Products-Mediated Signaling Pathways

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

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

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