Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase

Takemoto, Masao; Sun, Jianxin; Hiroki, Junko; Shimokawa, Hiroaki; Liao, James K.

doi:10.1161/01.cir.0000020682.73694.ab

Cited by 433 publications

(354 citation statements)

References 35 publications

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“…105 Activation of the RhoA/ROCK pathway impairs NO bioavailability through inhibition of eNOS mRNA stability, eNOS posphorylation at Ser 1177 and the Akt/PI3K pathway and enhancement of eNOS phosphorylation at Thr495. [106][107][108] Endothelial function and hypertension in aging Y Higashi et al Several investigators have shown an interaction between the RhoA/ ROCk pathway and ROS. 109,110 Indeed, ROS induced by hyperglycemia enhances ROCK activity, leading to atherothrombogenesis through an increase in expression of plasminogen activator inhibitor-1 in vascular endothelial cells.…”

Section: Tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

Endothelial dysfunction and hypertension in aging

2012

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Hypertension is one of the common diseases in the elderly. The prevalence of hypertension markedly increases with advancing age. Both aging and hypertension have a critical role in cardiovascular and cerebrovascular complications. Although aging and hypertension, either independently or collectively, impair endothelial function, aging and hypertension may have similar cascades for the pathogenesis and development of endothelial dysfunction. Nitric oxide (NO) has an important role in regulation of vascular tone. Decrease in NO bioavailability by endothelial dysfunction would lead to elevation of blood pressure. An imbalance of reduced production of NO or increased production of reactive oxygen species, mainly superoxide, may promote endothelial dysfunction. One possible mechanism by which the prevalence of hypertension is increased in relation to aging may be advancing endothelial dysfunction associated with aging through an increase in oxidative stress. In addition, endothelial cell senescence is also involved in aging-related endothelial dysfunction. In this review, we focus on recent findings and interactions between endothelial function, oxidative stress and hypertension in aging.

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Section: Tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

Endothelial dysfunction and hypertension in aging

2012

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“…Rho kinase is implicated in the pathophysiology of atherosclerosis (Miyata et al, 2000), myocardial infarction, and hypertension (Uehata et al, 1997). Activation of Rho kinase in endothelial cells under hypoxic conditions (Wolfrum et al, 2004) has been related to the mechanism responsible for the downregulation of eNOS during and after ischemia (Takemoto et al, 2002;Ming et al, 2002;Wolfrum et al, 2004;Jin et al, 2006).…”

Section: Rho Kinase (Rock)-inhibitorsmentioning

confidence: 99%

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Terpolilli¹,

Moskowitz

Plesnila³

2012

J Cereb Blood Flow Metab

122

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Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

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“…Since Rho-kinase inhibited the expression and activity of eNOS (Takemoto et al 2002;Sauzeau et al 2003), we examined the effects of fasudil on eNOS expression and activity in WT mice. As expected, long-term treatment with fasudil significantly enhanced eNOS phosphorylation, expression and activity (as evaluated by phosphorylated/ total eNOS) in the liver of HFD-fed WT mice (Fig.…”

Section: Fasudil Increases Enos Expression and Phosphorylation In Hfdmentioning

confidence: 99%

“…NO and Rho-kinase are known to negatively interact each other in vasomotor regulation (Takemoto et al 2002). Rho-kinase suppresses eNOS expression through destabilization of eNOS mRNA, while NO inhibits RhoA expression and Rho-kinase activity through the cGMP and protein kinase G (PKG) pathway (Sauzeau et al 2003;Kato et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Opposing Roles of Nitric Oxide and Rho-Kinase in Lipid Metabolism in Mice

Noda

Godo

Saito

et al. 2015

Tohoku J. Exp. Med.

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Dyslipidemia is a life-style disorder and is one of the important risk factors of cardiovascular diseases. Nitric oxide (NO) exerts beneficial effects on lipid metabolism through activation of hepatic sterol regulatory element-binding protein (SREBP)-2, a transcriptional factor for cholesterol metabolism and expression of LDL receptor, while Rho-kinase, an effecter protein of small G protein, RhoA, contributes to the pathogenesis of metabolic syndrome through suppressing the whole body energy consumption. However, the crosstalk between NO and Rho-kinase in regulation of lipid metabolism remains to be elucidated. In the present study, we used male wild-type (WT) mice and mice lacking three isoforms of NO synthase (NOSs −/− ). WT mice were fed either normal diet (ND) or high-fat diet (HFD), while NOSs −/− mice were fed ND with or without a selective Rho-kinase inhibitor, fasudil (100 mg/kg/day), for 6 weeks. At 6 weeks, plasma NOx concentration was significantly decreased and Rho-kinase activity and lipid levels were significantly elevated in HFD-fed WT mice and NOSs −/− mice compared with ND-fed WT mice. In the liver, SREBP-2 activity was reduced in NOSs −/− mice. Fasudil ameliorated lipid levels in HFD-fed WT mice and NOSs −/− mice without affecting SREBP-2 activity or LDL receptor expression, whereas it significantly enhanced phosphorylation of AMP-activated kinase (AMPK) in the liver and skeletal muscle. Importantly, the beneficial metabolic effects of fasudil were absent in HFD-fed AMPK −/− mice. These results provide the first evidence that NO and Rho-kinase play opposing roles for the lipid metabolism, suggesting that Rho-kinase inhibitors could be novel therapeutic agents of dyslipidemia.

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Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase

Cited by 433 publications

References 35 publications

Endothelial dysfunction and hypertension in aging

Endothelial dysfunction and hypertension in aging

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Opposing Roles of Nitric Oxide and Rho-Kinase in Lipid Metabolism in Mice

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