Rho Kinase: An Important Mediator of Atherosclerosis and Vascular Disease

Zhou, Qian; Liao, James K.

doi:10.2174/138161209789057986

Cited by 102 publications

(76 citation statements)

References 97 publications

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“…26 Coincident with these finding, our data revealed that knockdown of RhoA was capable of increasing p53 protein levels and inhibiting VEGF expression, but the inhibition of VEGF mediated by siRhoA was abolished after p53 knockdown.…”

Section: Discussionsupporting

confidence: 79%

Ras homolog gene family, member A promotes p53 degradation and vascular endothelial growth factor‐dependent angiogenesis through an interaction with murine double minute 2 under hypoxic conditions

Xue

Cui

et al. 2012

Cancer

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BACKGROUND: Tumor neovascularization (TNV) is a common pathologic basis for malignant growth and metastasis. However, the mechanism of TNV pathogenesis is not fully understood. Ras homolog gene family, member A (RhoA), a Rho guanosine triphosphatase (GTPase) family member, may be involved in a hypoxia-induced vascular endothelial growth factor (VEGF) pathway that regulates TNV angiogenesis through an unclear mechanism. METHODS: The regulation of RhoA on p53, the p53 binding protein homolog murine double minute 2 (MDM2), and VEGF was analyzed in hypoxic MCF-7 cells using Western blot analysis, real-time polymerase chain reaction (PCR) analysis, coimmunoprecipitation, and immunofluorescence staining assays. Changes in proliferation, invasion, migration, stress fiber formation, and tube formation were detected in an MCF-7 human umbilical vein endothelial cell (HUVEC) coculture system. Correlations of RhoA expression with MDM2, wild-type p53 (wt-p53), and VEGF expression in breast cancer tissues and relations between RhoA and breast cancer clinical features were analyzed by immunohistochemistry. RESULTS: Activated RhoA down-regulated p53 protein, which increased VEGF expression in hypoxic MCF-7 cells; whereas p53 messenger RNA levels were not altered. In addition, the ubiquitin-mediated degradation of p53 was enhanced by active RhoA. RhoA and MDM2 colocalized in the cytoplasm of hypoxic MCF-7 cells and interacted with each other physically. Furthermore, nutlin-3, a specific MDM2 inhibitor, was capable of reducing activated RhoA-induced p53 protein stability and attenuating VEGF accumulation. In an MCF-7-HUVEC coculture system, nutlin-3 effectively inhibited HUVEC proliferation, invasion, migration, stress fiber formation, and tube formation mediated by activated RhoA under hypoxic conditions. Data from 129 clinical breast cancer specimens with wt-p53 revealed that high RhoA expression was correlated with high MDM2 expression, low wt-p53 expression, and high VEGF expression. CONCLUSIONS: The current data suggested that activated RhoA promotes VEGF expression and hypoxia-induced angiogenesis through the up-regulation of MDM2 to decrease p53 stability. Cancer 2012;118:4105-16.

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Section: Discussionsupporting

confidence: 79%

Ras homolog gene family, member A promotes p53 degradation and vascular endothelial growth factor‐dependent angiogenesis through an interaction with murine double minute 2 under hypoxic conditions

Xue

Cui

et al. 2012

Cancer

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“…Using a cell culture model, we reproduced the report that KCl stimulates myocardin mRNA expression and the expression of its target genes through the RhoA-ROCK pathway in vascular SMCs. 11 Because ATV is well known to inhibit the RhoA-ROCK pathway in various cell types, including vascular SMCs, 23 our observation that ATV inhibits KCl- induced myocardin expression has further substantiated a novel mechanism underlying direct inhibition of vessel contractility by ATV or other statins. Finally, our results showing inhibition of RhoA activation and membrane translocation by ATV and its prevention by Meva further support the involvement of the RhoA-ROCK pathway.…”

Section: Discussionmentioning

confidence: 79%

Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells

Jiang²,

Yin³

et al. 2012

Hypertension

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Abstract-Atorvastatin (ATV), an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, is widely prescribed as a lipid-lowering drug. It also inhibits the RhoA-Rho-associated kinase pathway in vascular smooth muscle (SM) cells and critically inhibits SM function. Myocardin is a coactivator of serum response factor, which upregulates SM contractile proteins. The RhoA-Rho-associated kinase pathway, which directly triggers SM contraction, also increases myocardin gene expression. Therefore, we investigated whether ATV inhibits myocardin gene expression in SM cells. In mice injected with ATV (IP 20 g/g per day) for 5 days, myocardin gene expression was significantly downregulated in aortic and carotid arterial tissues with decreased expression of myocardin target genes SM ␣-actin and SM22. Correspondingly, the contractility of aortic rings in mice treated with ATV or the Rho-associated kinase inhibitor Y-27632 was reduced in response to treatment with either KCl or phenylephrine. In cultured mouse and human aortic SM cells, KCl treatment stimulated the expression of myocardin, SM ␣-actin, and SM22. These stimulatory effects were prevented by ATV treatment. ATV-induced inhibition of myocardin expression was prevented by pretreatment with either mevalonate or geranylgeranylpyrophosphate but not farnesylpyrophosphate. Treatment with Y-27632 mimicked ATV effects on the gene expression of myocardin, SM ␣-actin, and SM22, further suggesting a role for the RhoA-Rho-associated kinase pathway in ATV effects. Furthermore, ATV treatment inhibited RhoA membrane translocation and activation; these effects were prevented by pretreatment with mevalonate. We conclude that ATV inhibits myocardin gene expression in vivo and in vitro, suggesting a novel mechanism for ATV inhibition of vascular contraction. Statins inhibit production of isoprenoid intermediates in the cholesterol biosynthetic pathway, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), to reduce posttranslational modifications of several intracellular signaling proteins, including nuclear lamins, Ras, Rho, Rac, and Rap. 1-3 The Ras and Rho GTPase family members are the major substrates for posttranslational modification by prenylation. 4 These small GTP-binding proteins cycle between the inactive GDP-bound state and active GTP-bound state and play critical roles in the regulation of the actin cytoskeleton and intracellular signaling pathways. It has been shown that statins regulate subcellular location 1 and activation of Ras and Rho. 5 The inhibitory effect of statins on prenylation of these small G proteins, for example, RhoA, and, therefore, the RhoA-Rho-associated kinase (ROCK) pathway, is known to contribute to protection of the cardiovascular system beyond their cholesterol-lowering effects. 6 It is well known that the ROCK pathway stimulates contraction through inhibition of myosin light-chain phosphatase or phosphorylation of myosin light chain 20. 7,8 Statins attenuate spontaneous smooth muscle (SM) tone through inhibition of the...

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“…Excessive RhoA/Rhokinase activity may lead to a decrease in NO synthesis and to endothelial dysfunction and RhoA/Rhokinase inhibitors to reverse this have made RhoA/Rhokinase pathway an important therapeutic target in cardiovascular treatment [38].…”

Section: Discussionmentioning

confidence: 99%

Effects of At2 Receptor Agonist Novokinin on Oxidative Stress, Inflammation and Infarct Size Due to Myocardial Ischemia-Reperfusion

E¹,

Şahna²

2017

JBiSE

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Aim: Ischemia and reperfusion (IR) injury is a serious problem that is occurred during thrombolytic therapy, organ transplantation, coronary angioplasty, and cardiopulmonary bypass. There is an increase in the number of AT2 receptors in some pathological conditions such as cardiac hypertrophy, myocardial infarction, congestive heart failure. This study was designed to investigate the effects AT2 receptor agonist Novokinin on infarct size, caveolin-1 (CAV-1), HSP90, ADMA, NADPH oxidase and Rhokinase associated to endothelial dysfunction and oxidative stress, and NFκB and TLR-4 levels induced by inflammation on myocardial IR. Methods: The experimental groups: Sham (C), Novokinin (N), IR and IRN. Novokinin was performed with infusion pump before ischemia, and during IR. The left main coronary artery was occluded for 30 minutes ischemia followed by 120 minutes reperfusion in anesthetized rats. CAV-1, HSP90, and NFκB levels were measured by the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), ADMA, TLR-4, NADPH oxidase, and Rhokinase levels were measured by ELISA, infarct size was measured by ImageJ, an image analysis software, in the heart tissue. Results: NFκB, HSP90, NADPH oxidase and TLR-4 levels increased with IR and significantly decreased with Novokinin. CAV-1 levels were not different between the groups. ADMA and Rhokinase levels were increased due to IR but decreased with Novokinin. Novokinin reduced infarct size due to IR. Conclusion: Our results showed that, ADMA, HSP90, NFκB, TLR-4, Rhokinase, and NADPH oxidase levels play important roles on IR injury. AT2 receptor agonist Novokinin may affect positively oxidative changes, inflammation, and endothelial function in myocardial IR injury.

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Rho Kinase: An Important Mediator of Atherosclerosis and Vascular Disease

Cited by 102 publications

References 97 publications

Ras homolog gene family, member A promotes p53 degradation and vascular endothelial growth factor‐dependent angiogenesis through an interaction with murine double minute 2 under hypoxic conditions

Ras homolog gene family, member A promotes p53 degradation and vascular endothelial growth factor‐dependent angiogenesis through an interaction with murine double minute 2 under hypoxic conditions

Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells

Effects of At2 Receptor Agonist Novokinin on Oxidative Stress, Inflammation and Infarct Size Due to Myocardial Ischemia-Reperfusion

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