C-Reactive Protein Adversely Alters the Protein–Protein Interaction of the Endothelial Isoform of Nitric Oxide Synthase

Valleggi, Simona; Devaraj, Sridevi; Dasu, Mohan R.; Jialal, Ishwarlal

doi:10.1373/clinchem.2009.142364

Cited by 14 publications

(10 citation statements)

References 18 publications

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“…Earlier observations demonstrated that CRP levels correlated inversely with endothelial vasoreactivity. The most compelling data implicating CRP as a determinant of endothelial dysfunction were studies demonstrating that human CRP reduced basal and stimulated nitric oxide release from arterial and venous endothelial cells [9, 10]. In human aortic endothelial cells (HAEC), CRP resulted in significant reduction in mRNA and protein for endothelial nitric oxide synthase (eNOS).…”

Section: Introductionmentioning

confidence: 99%

“…In human aortic endothelial cells (HAEC), CRP resulted in significant reduction in mRNA and protein for endothelial nitric oxide synthase (eNOS). Furthermore, CRP reduced eNOS activity (ie, conversion of L-arginine to L-citrulline) and bioactivity (secretion of cyclic guanosine 5′-monophosphate [cGMP]), in part through decreasing eNOS mRNA stability [9, 10]. CRP mediates uncoupling of eNOS via stimulation of NADPH oxidase and inhibition of GTP cyclohydrolase [11].…”

Section: Introductionmentioning

confidence: 99%

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Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP?

Devaraj

Siegel

Jialal

2010

Curr Atheroscler Rep

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Much evidence supports a pivotal role for inflammation in atherosclerosis. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a cardiovascular risk marker and may also promote atherogenesis. CRP levels are increased in metabolic syndrome and hypertension and confer increased risk of cardiovascular events in patients in these subgroups. Statins have been shown to lower low-density lipoproteins and CRP independently, and reduce cardiovascular events in subjects with and without metabolic syndrome and hypertension. In this review, we focus on the results from the primary prevention statin trial, Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which showed reductions in LDL, CRP, and cardiovascular events. Post-JUPITER, the new guidelines will now need to consider recommending high-sensitivity CRP testing to intermediate-risk metabolic syndrome patients and those with hypertension and intermediate risk so that we can better identify candidates at greater risk and reduce cardiovascular burden in these subjects with statin therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP?

Devaraj

Siegel

Jialal

2010

Curr Atheroscler Rep

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“…3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors can improve the impaired endothelial dysfunction of the aorta in spontaneously hypertensive rats and may activate eNOS by phosphorylation and a decrease of Cav-1 abundance (131). In contrast, a 24-h treatment of C-reactive protein increased eNOS binding to Cav-1 in human aortic endothelial cells, thereby negatively regulating eNOS (141). Methyl-␤-cyclodextrin can inhibit caveolae-mediated endocytosis by moving cholesterol out of lysosomes and prevent eNOS-dependent NO production at the same time (80).…”

Section: Caveolins and Coexpression Partnersmentioning

confidence: 96%

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang¹,

Janssens

Wingler

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Zhang Y, Janssens SP, Wingler K, Schmidt HH, Moens AL. Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am J Physiol Heart Circ Physiol 301: H634 -H646, 2011. First published May 27, 2011 doi:10.1152/ajpheart.01315.2010.-The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.endothelial nitric oxide synthase uncoupling; modulators; superoxide; tetrahydrobiopterin; enhancers; nitric oxide donors THE REVALENCE AND SEVERITY of incipient or overt cardiovascular diseases associated with reduced nitric oxide (NO) bioavailability has resulted in efforts to restore and conserve adequate NO signaling in the heart and blood vessels through therapeutic interventions. In the cardiovascular system, the signaling molecule NO, which is produced by the enzyme endothelial NO synthase (eNOS, NOS3), has a crucial role in maintaining normal vascular function, mediated by its vasodilating capacity and through a variety of antiatherogenic effects. eNOS is not only expressed in endothelial cells of the heart and blood vessels, in both atrial and ventricular myocytes, but also in specialized pacemaker tissue.Uncoupling of bioactive, i.e., dimeric eNOS to an inactive monomeric form (73) is caused by oxidative stress, which reduces the bioavailability of tetrahydrobiopterin (BH 4 ), an essential cofactor of eNOS. In this uncoupled state, NADPH consumption and oxygen reduction are uncoupled from L-arginine oxidation and NO formation with a subsequently decreased NO production and increased superoxide generation (157). eNOS generated superoxide, further oxidizes BH 4 , and hence enhances the uncoupling of eNOS. However, it is unclear which source of superoxide initiates eNOS uncoupling.Uncoupling of eNOS has been described in 1) situations associated with endothelial dysfunction such as atherosclerosis (3, 70), diabetes mellitus (135), ischemia-reperfusion (I/R) injury (35,138), hypertension (68), and chronic flow overload (78); 2) cardiac hypertrophy with ventricular remodeling (133); and 3) diastolic heart failure (149). eNOS also uncouples physiologically. For example, eNOS may uncouple postnatal in the lung, possibly leading to a developmental adaptation of the pulmonary vascular system to produce reactive oxygen species (ROS) (81). In addition, it ...

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“…Hsp90 promotes these phosphorylation events by potentially increasing the binding affinity for eNOS and Akt and causing a conformational shift that unmasks sites for modification [60, 61]. Several eNOS agonists stimulate rapid eNOS-hsp90 interaction and blockade of this partnership limits NO production and vasorelaxation [55, 62] with pathological conditions leading to a decrease in the association of these two proteins [63, 64]. …”

Section: Regulation Of No Production: the Dynamic Modulation Of Enosmentioning

confidence: 99%

Compartmentalized nitric oxide signaling in the resistance vasculature

Mutchler¹,

Straub

2015

Nitric Oxide

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Nitric oxide (NO) was first described as a bioactive molecule through its ability to stimulate soluble guanylate cyclase, but the revelation that NO was the endothelium derived relaxation factor drove the field to its modern state. The wealth of research conducted over the past 30 years has provided us with a picture of how diverse NO signaling can be within the vascular wall, going beyond simple vasodilation to include such roles as signaling through protein S-nitrosation. This expanded view of NO’s actions requires highly regulated and compartmentalized production. Importantly, resistance arteries house multiple proteins involved in the production and transduction of NO allowing for efficient movement of the molecule to regulate vascular tone and reactivity. In this review, we focus on the many mechanisms regulating NO production and signaling action in the vascular wall, with a focus on the control of endothelial nitric oxide synthase (eNOS), the enzyme responsible for synthesizing most of the NO within these confines. We also explore how cross talk between the endothelium and smooth muscle in the microcirculation can modulate NO signaling, illustrating that this one small molecule has the capability to produce a plethora of responses.

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C-Reactive Protein Adversely Alters the Protein–Protein Interaction of the Endothelial Isoform of Nitric Oxide Synthase

Cited by 14 publications

References 18 publications

Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP?

Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP?

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Compartmentalized nitric oxide signaling in the resistance vasculature

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