Angiotensin II Type I Receptor Blocker and Endothelial Function in Humans: Role of Nitric Oxide and Oxidative Stress

Higashi, Yukihito; Chayama, Kazuaki; Yoshizumi, Masao

doi:10.2174/1568016053544363

Cited by 33 publications

(23 citation statements)

References 137 publications

(275 reference statements)

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“…It is well known that NAPDH oxidase is composed of cytosolic components, such as p47phox, p67phox, and RC1, and membrane-spanning components, such as p22phox and gp91phox. Angiotensin II -induced NADPH oxidase activation is one of the major sources of ROS in the pathophysiologic mechanism of atherosclerosis (35,36). These observations are consistent with the findings of the present study, in which angiotensin II induced the expression of p47phox and production of the O 2 À radical.…”

Section: Discussionsupporting

confidence: 93%

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Angiotensin II Induces Oxidative Stress in Prostate Cancer

Uemura

Ishiguro

et al. 2008

Molecular Cancer Research

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Angiotensin II has been shown to be a cytokine especially acting as a growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of angiotensin II seems to be similar in prostate cancer, as we previously reported. In the present study, we explored the biological role of angiotensin II in oxidative stress of prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related proteins (p47phox, manganese superoxide dismutase 2, glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with angiotensin II and/or an angiotensin II receptor type 1 blocker, candesartan. To examine DNA damage induced by angiotensin II, 8-hydroxy-2 ¶-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint proteins including p53, Chk2, and cdc2. Immunocytochemical studies of inducible nitric oxide synthase and superoxide anion radical (O 2 À ) were done in LNCaP cells stimulated with angiotensin II. The phosphorylation of Akt was induced by angiotensin II treatment and inhibited by candesartan, as well as by LY294002, an inhibitor of phosphoinositide 3-kinase. Oxidative stress-related proteins were up-regulated by angiotensin II and inhibited by pretreatment with candesartan or catalase. The level of 8-hydroxy-2 ¶-deoxyguanosine was increased by angiotensin II and conversely decreased by candesartan. Immunocytochemical studies showed that angiotensin II enhanced an inflammatory marker, inducible nitric oxide synthase, and the production of O 2 À radical. The hypothesis that angiotensin II has the potential to induce oxidative stress, which may be implicated in carcinogenesis of the prostate gland through long-term exposure to chronic inflammation is proposed. (Mol Cancer Res 2008;6(2):250 -8)

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Section: Discussionsupporting

confidence: 93%

“…5. Higashi et al confirmed that NADPH oxidase is the most important source of ROS in the vasculature (35). It is well known that NAPDH oxidase is composed of cytosolic components, such as p47phox, p67phox, and RC1, and membrane-spanning components, such as p22phox and gp91phox.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Induces Oxidative Stress in Prostate Cancer

Uemura

Ishiguro

et al. 2008

Molecular Cancer Research

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“…Modrick et al (2009) showed that in the absence of AT1, endothelial dysfunction did not occur in old mice, suggesting a novel and fundamental role for Ang II in age-related vascular dysfunction. While it is well established that Ang II produces oxidative stress in various tissues (Higashi et al 2005;Lassegue et al 2001;Seshiah et al 2002), the relative importance of Ang II and its ability to induce signaling that leads to vascular dysfunction with aging has been less well explored.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Kim

Heo

et al. 2011

AGE

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Angiotensin II (Ang II), a major effector of the renin-angiotensin system, is now recognized as a pro-inflammatory mediator. This Ang II signaling, which causes transcription of pro-inflammatory genes, is regulated through nuclear factor-κB (NF-κB). At present, the molecular mechanisms underlying the effect of aging on Ang II signaling and NF-κB activation are not fully understood. The purpose of this study was to document altered molecular events involved in agerelated changes in Ang II signaling and NF-κB activation. Experimentations were carried out using kidney tissues from Fischer 344 rats at 6, 12, 18, and 24 months of age, and the rat endothelial cell line, YPEN-1 for the detailed molecular work. Results show that increases in Ang II and Ang II type 1 receptor during aging were accompanied by the generation of reactive species. Increased Ang II activated NF-κB by phosphorylating IκBα and p65. Increased phosphorylation of p65 at Ser 536 was mediated by the enhanced phosphorylation of IκB kinase αβ, while phosphorylation site Ser 276 of p65 was mediated by upregulated mitogen-activated and stress-activated protein kinase-1. These altered molecular events in aged animals were partly verified by experiments using YPEN-1 cells. Collectively, our findings provide molecular insights into the pro-inflammatory actions of Ang II, actions that influence the phosphorylation of p65-mediated NF-κB activation during aging. Our study demonstrates the age-related pleiotropic nature of the physiologically important Ang II can change into a deleterious culprit that contributes to an increased incidence of many chronic diseases such as atherosclerosis, diabetes, and dementia.

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“…This is in agreement with previous reports showing the positive effect of blocking the converting enzyme or the AT1R on endothelial function. 38 ROS have a key role in the signaling pathways activated by angiotensin II in vascular cells. Therefore, we tested the involvement of ROS in LF remodeling.…”

Section: Discussionmentioning

confidence: 99%

Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries

et al. 2010

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Blood flow reduction induces inward remodeling of resistance arteries (RAs). This remodeling occurs in ischemic diseases, diabetes and hypertension. Nonetheless, the effect of flow reduction per se, independent of the effect of pressure or metabolic influences, is not well understood in RA. As angiotensin II is involved in the response to flow in RA, we hypothesized that angiotensin II may also be involved in the remodeling induced by a chronic flow reduction. We analyzed the effect of angiotensin I-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) on inward remodeling induced by blood flow reduction in vivo in rat mesenteric RAs (low flow (LF) arteries). After 1 week, diameter reduction in LF arteries was associated with reduced endothelium-dependent relaxation and lower levels of eNOS expression. Superoxide production and extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation were higher in LF than in normal flow arteries. Nevertheless, the absence of eNOS or superoxide level reduction (tempol or apocynin) did not prevent LF remodeling. Perindopril and candesartan prevented inward remodeling in LF arteries. Contractility to angiotensin II was reduced in LF vessels by perindopril, candesartan and the ERK1/2 blocker PD98059. ERK1/2 activation (ratio phospho-ERK/ERK) was higher in LF arteries, and this activation was prevented by perindopril and candesartan. ERK1/2 inhibition in vivo (U0126) prevented LF-induced diameter reduction. Thus, inward remodeling because of blood flow reduction in mesenteric RA depends on unopposed angiotensin II-induced contraction and ERK1/2 activation, independent of superoxide production. These findings might be of importance in the treatment of vascular disorders.

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Angiotensin II Type I Receptor Blocker and Endothelial Function in Humans: Role of Nitric Oxide and Oxidative Stress

Cited by 33 publications

References 137 publications

Angiotensin II Induces Oxidative Stress in Prostate Cancer

Angiotensin II Induces Oxidative Stress in Prostate Cancer

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries

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