A Specific Role for eNOS-Derived Reactive Oxygen Species in Atherosclerosis Progression

Takaya, Tomofumi; Hirata, Ken‐ichi; Yamashita, Tomoya; Shinohara, Masakazu; Sasaki, Naoto; Inoue, N.; Yada, Toyotaka; Goto, Masami; Fukatsu, Atsushi; Hayashi, Toshio; Nicholas, J.; Channon, Keith M.; Yokoyama, Mitsuhiro; Kawashima, Seinosuke

doi:10.1161/atvbaha.107.142182

Cited by 81 publications

(64 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PE enhanced the cGMP level significantly in WT mice but not apoE-KO mice (Fig. 8B), suggesting that the NO/cGMP signaling mechanism compensatively increased in aortas from apoE-KO mice in early atherosclerosis, as reported previously 45,46) . The reason why PE does not raise the cGMP level of aortas from apoE-KO mice so much is unclear.…”

Section: Discussionsupporting

confidence: 86%

Role of Rho/Rho-Kinase and NO/cGMP Signaling Pathways in Vascular Function Prior to Atherosclerosis

Mori-Kawabe

Tsushima

Fujimoto

et al. 2009

JAT

View full text Add to dashboard Cite

Aim: Atherosclerosis is a cardiovascular disease; however, there is little information on signal transduction for vascular function in the early stage of atherosclerosis. In this work, we investigated the role of Rho/Rho-kinase and nitrogen oxide (NO)/cyclic GMP (cGMP) signaling pathways in the aorta prior to atherosclerosis. Methods: Tension, the expression of RhoA protein, Rho-kinase activity and the cGMP level were measured using endothelium-intact or -denuded aorta prepared from apolipoprotein E-deficient (apoE-KO) and C57BL/6 wild-type (WT) mice at 2 months of age. Results: Phenylephrine (PE) induced less maximal contraction in the endothelium-denuded aorta from apoE-KO than from WT mice. A Rho-kinase inhibitor (Y-27632) reduced more effectively the contraction of apoE-KO than WT mice, but their RhoA proteins and Rho-kinase activities were not so different. Acetylcholine caused larger relaxation of the PE-stimulated, endothelium-intact aorta in apoE-KO due to endothelial NO release than WT mice. The basal cGMP level in the endotheliumintact aorta of apoE-KO mice was higher than that of WT. Conclusions: Smooth muscle contraction via 1-adrenergic receptor shows higher dependency on Rho-kinase activity, suggesting down-regulation of the mechanism different from Rho/Rho kinase signaling in the aorta prior to atherosclerosis. Endothelium-dependent relaxation is also intensified through the NO/cGMP pathway.

show abstract

Section: Discussionsupporting

confidence: 86%

Role of Rho/Rho-Kinase and NO/cGMP Signaling Pathways in Vascular Function Prior to Atherosclerosis

Mori-Kawabe

Tsushima

Fujimoto

et al. 2009

JAT

View full text Add to dashboard Cite

show abstract

“…Based on these findings, GTPCH1 is reported to be a potential and rational target to augment endothelial BH4 in reversing eNOS activity in endothelial dysfunctional states. Recently, Takaya et al [42] showed that augmenting BH4 levels in the endothelium by GTPCH1 overexpression reduces atherosclerosis in apoE KO/eNOS Tg mice and is associated with a reduction in O 2 -from uncoupled eNOS. In the present study, we focused on the effects of CRP on intracellular BH4 levels.…”

Section: Discussionmentioning

confidence: 99%

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Singh

Devaraj

Vásquez‐Vivar

et al. 2007

Journal of Molecular and Cellular Cardiology

119

View full text Add to dashboard Cite

C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. We have previously shown that CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). In this study, we examined the mechanisms by which CRP decreases eNOS activity in HAECs. To this end, we explored different strategies such as availability of tetrahydrobiopterin (BH4) -a critical cofactor for eNOS, superoxide (O 2 -) production resulting in uncoupling of eNOS and phosphorylation/dephosphorylation of eNOS. CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. Pretreatment with sepiapterin, a BH4 precursor, prevented CRP-mediated effects on BH 4 levels, superoxide production as well as eNOS activity. The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH 4 , was significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP mediated pathway. In the present study, CRP mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. Furthermore, CRP-induced O 2 -production was reversed by pharmacologic inhibition and siRNAs to p47 phox and p22 phox. Additionally, CRP treatment significantly decreased the eNOS dimer:monomer ratio confirming CRP-mediated eNOS uncoupling. The pretreatment of cells with NO synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]) also prevented CRP-mediated O 2 -production further strengthening CRP-mediated eNOS uncoupling. Additionally, CRP decreased eNOS phosphorylation at Ser1177 as well as increased phosphorylation at Thr495. CRP appears to mediate these effects through the Fcγ receptors, CD32 and CD64.To conclude, CRP uncouples eNOS resulting in increased superoxide production, decreased NO production, altered eNOS phosphorylation.

show abstract

“…93,94 Recent clinical data also indicates that variants of GTP cyclohydrolase I are governing NO production, autonomic activity and even cardiovascular risk. 95 With respect to hypertension, an important study by Du et al 96 showed that increased oxidative stress due to eNOS uncoupling may directly affect blood pressure.…”

Section: Ros Sources In Hypertension Nadph Oxidasesmentioning

confidence: 99%

Oxidative stress and endothelial dysfunction in hypertension

2011

View full text Add to dashboard Cite

Systemic arterial hypertension is a highly prevalent cardiovascular risk factor that causes significant morbidity and mortality, and is becoming an increasingly common health problem because of the increasing longevity and prevalence of predisposing factors such as sedentary lifestyle, obesity and nutritional habits. Further complicating the impact of this disease, mild and moderate hypertension are usually asymptomatic, and their presence (and the subsequent increase in cardiovascular risk) is often unrecognized. The pathophysiology of hypertension involves a complex interaction of multiple vascular effectors including the activation of the sympathetic nervous system, of the renin-angiotensin-aldosterone system and of the inflammatory mediators. Subsequent vasoconstriction and inflammation ensue, leading to vessel wall remodeling and, finally, to the formation of atherosclerotic lesions as the hallmark of advanced disease. Oxidative stress and endothelial dysfunction are consistently observed in hypertensive subjects, but emerging evidence suggests that they also have a causal role in the molecular processes leading to hypertension. Reactive oxygen species (ROS) may directly alter vascular function or cause changes in vascular tone by several mechanisms including altered nitric oxide (NO) bioavailability or signaling. ROS-producing enzymes involved in the increased vascular oxidative stress observed during hypertension include the NADPH oxidase, xanthine oxidase, the mitochondrial respiratory chain and an uncoupled endothelial NO synthase. In the current review, we will summarize our current understanding of the molecular mechanisms in the development of hypertension with an emphasis on oxidative stress and endothelial dysfunction.

show abstract

A Specific Role for eNOS-Derived Reactive Oxygen Species in Atherosclerosis Progression

Cited by 81 publications

References 30 publications

Role of Rho/Rho-Kinase and NO/cGMP Signaling Pathways in Vascular Function Prior to Atherosclerosis

Role of Rho/Rho-Kinase and NO/cGMP Signaling Pathways in Vascular Function Prior to Atherosclerosis

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Oxidative stress and endothelial dysfunction in hypertension

Contact Info

Product

Resources

About