Adherence of uremic erythrocytes to vascular endothelium decreases endothelial nitric oxide synthase expression

Bonomini, Mario; Pandolfi, Assunta; Pietro, Natalia Di; Sirolli, Vittorio; Giardinelli, Annalisa; Consoli, Agostino; Amoroso, Luigi; Gizzi, F.; Lutiis, Maria Anna De; Felaco, Mario

doi:10.1111/j.1523-1755.2005.00288.x

Cited by 23 publications

(26 citation statements)

References 44 publications

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“…Again, we have previously demonstrated that phosphatidylserine exposure on the surface of RBC from ESRD patients increases RBC-human umbilical vein endothelial cell interactions, thus suggesting that modified ESRDRBCs might also show abnormal RBC-NOS activation, possibly due to enhanced cytoadherence and locally increased mechanical forces [20,49,50]. Subsequently, we demonstrated that RBC-NOS from ESRD-RBCs disrupted the eNOS/cav-1 interaction on the plasma membrane and increased CaM binding, possibly activating the enzyme and inducing translocation to the cytoplasm where eNOS bound to HSP90 became more phosphorylated and synthesized more NO (Figs.…”

Section: Discussionmentioning

confidence: 90%

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Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients

et al. 2016

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Red blood cells (RBCs) enzymatically produce nitric oxide (NO) by a functional RBC-nitric oxide synthase (RBC-NOS). NO is a vascular key regulatory molecule. In RBCs its generation is complex and influenced by several factors, including insulin, acetylcholine, and calcium. NO availability is reduced in end-stage renal disease (ESRD) and associated with endothelial dysfunction. We previously demonstrated that, through increased phosphatidylserine membrane exposure, ESRD-RBCs augmented their adhesion to human cultured endothelium, in which NO bioavailability decreased. Since RBC-NOS-dependent NO production in ESRD is unknown, this study aimed to investigate RBC-NOS levels/activation, NO production/bioavailability in RBCs from healthy control subjects (C, N = 18) and ESRD patients (N = 27). Although RBC-NOS expression was lower in ESRDRBCs, NO, cyclic guanosine monophosphate (cGMP), RBC-NOS Serine1177 phosphorylation level and eNOS/ Calmodulin (CaM)/Heat Shock Protein-90 (HSP90) interaction levels were higher in ESRD-RBCs, indicating increased enzyme activation. Conversely, following RBCs stimulation with insulin or ionomycin, NO and cGMP levels were significantly lower in ESRD-than in C-RBCs, suggesting that uremia might reduce the RBC-NOS response to further stimuli. Additionally, the activity of multidrug-resistance-associated protein-4 (MRP4; cGMPmembrane transporter) was significantly lower in ESRDRBCs, suggesting a possible compromised efflux of cGMP across the ESRD-RBCs membrane. This study for the first time showed highest basal RBC-NOS activation in ESRDRBCs, possibly to reduce the negative impact of decreased NOS expression. It is further conceivable that high NO production only partially affects cell function of ESRDRBCs maybe because in vivo they are unable to respond to physiologic stimuli, such as calcium and/or insulin.Keywords End-stage renal disease Á Red blood cells Á Nitric oxide Á cGMP Á Nitric oxide synthase Mario Bonomini, and Assunta Pandolfi have contributed equally to the study.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 90%

“…In fact, we have recently demonstrated that in ESRD patients the appearance of the PS on the RBC surface increases their adhesion to cultured human endothelial cells, resulting in decreased endothelial nitric oxide synthase (eNOS) expression and NO release from endothelium [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients

et al. 2016

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“…Interestingly, we observed that adhesion of RBCs from uremic patients to the vascular endothelium may modulate NO release by endothelial cultures (83), as previously demonstrated for sickle RBC (84). In cultured human endothelial cells, erythrocytes from uremic patients inhibited the eNOS expression (mRNA and protein), activity and, consequently, NO production, whereas erythrocytes from normal subjects had no such role (83). Defective eNOS is thought to represent a key parameter characterizing endothelial cell dysfunction, and in uremia it might have several consequences.…”

Section: Rbc-endothelial Cell Interactionmentioning

confidence: 81%

Erythrocyte Alterations and Increased Cardiovascular Risk in Chronic Renal Failure

et al. 2017

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Patients suffering from chronic renal failure have a higher burden of cardiovascular events, which increases in a dose-dependent fashion as renal function worsens. Increased cardiovascular risk in these patients is thought to be mediated by the simultaneous presence of both traditional and non-traditional cardiovascular risk factors, the latter being associated with renal impairment. Red blood cells are usually considered as carries of nutrients for tissues and respiratory gases, less so as compartments essential to vascular integrity. However, erythrocyte number, size, and integrity seem to severely affect cardiovascular morbidity and mortality as established in recent clinical studies with large patient cohorts. In particular, the role of red blood cells in chronic renal failure tends only to be considered exclusively in relation to a change in their number. However, these cells in the uremic milieu are prone to many alterations, which may adversely affect the cardiovascular system. In this review, we highlight the main qualitative erythrocyte alterations that may have a pathophysiologic role in the elevated cardiovascular risk of chronic renal failure.

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“…This inconsistency may be related to limitations in methodology -whole body production of an NO metabolite may not adequately reflect endothelial NO synthesis -or be explained by heterogeneity between patient groups, the latter underscoring the importance of better diagnostic tools to assess the NO system in the individual patient. Reduced NO production in uremic patients may be partially explained by the observation that adhesion of uremic erythrocytes to vascular endothelium causes a decrease in the levels of eNOS mRNA and protein, and inhibition of NOS activity [171]. A study in a chronic renal failure model showed enhanced caveolin-1 protein expression in aortic, liver and renal tissues, depressed Akt in aorta, heart and liver tissues, and reduced urinary cGMP levels after 6 weeks [172].…”

Section: Approach To the Patient With Ckdmentioning

confidence: 97%

Understanding eNOS for Pharmacological Modulation of Endothelial Function: A Translational View

Braam

Verhaar

2007

CPD

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Knowledge about the function of endothelial nitric oxide synthase (eNOS), and its regulation in pathophysiological states has tremendously increased. It is now clear that diminished activity of nitric oxide (NO) contributes to endothelial dysfunction, which is a characteristic of impeding atherosclerosis. This review aims to summarize the available knowledge about the impact of important cardiovascular risk factors on NO production by eNOS. There are 4 principle causes of diminished NO bio-activity: decreased expression and/or activity of the eNOS enzyme, eNOS uncoupling, enhanced breakdown or scavenging of NO and impaired transmission of NO-mediated signaling events (failure of the effector mechanisms). From the analysis, it becomes clear, that several aspects of eNOS functionality have only scarcely been tested under conditions of increased (experimental) cardiovascular risk. These aspects include palmitoylation, myristoylation and phosphorylation of the eNOS enzyme. Clear is that enhanced production of reactive oxygen species (ROS) and eNOS uncoupling are relatively important causes of reduced NO-bioactivity in cardiovascular disease states. Ideally, eNOS is sufficiently expressed, produces NO sufficiently and not abundantly, does not produce superoxide and is not scavenged by ROS; the produced NO then reaches its signaling target, mainly soluble guanylyl cyclase (sGC) and elicits a cellular response. Considering which aspects of eNOS are now assessable in a clinical setting and which therapeutic measures are available, there is a great challenge ahead.

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Adherence of uremic erythrocytes to vascular endothelium decreases endothelial nitric oxide synthase expression

Cited by 23 publications

References 44 publications

Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients

Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients

Erythrocyte Alterations and Increased Cardiovascular Risk in Chronic Renal Failure

Understanding eNOS for Pharmacological Modulation of Endothelial Function: A Translational View

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