Endocan — the new endothelial activation marker independently associated with soluble endothelial adhesion molecules in uraemic patients with cardiovascular disease

doi:10.1016/j.clinbiochem.2015.01.006

Clinical Biochemistry

Volume 48, Issue 6, April 2015, Pages 425-430

https://doi.org/10.1016/j.clinbiochem.2015.01.006 Get rights and content

Highlights

•
Endocan and sCAMs were increased in CKD patients.
•
Endocan and sCAMs were higher in CKD patients with CVD compared to those without CVD.
•
Endocan was associated with sCAMs only in CKD patients with CVD.
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Endocan was one of the predictors of sCAMs in CKD patients with CVD.

Abstract

Objectives

Endocan is a new marker of endothelial cell activation that mediates adhesion of leukocytes into endothelium. Soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules play an important role in the prevalence of cardiovascular disease (CVD) in chronic kidney disease (CKD) patients. The aim of this study is to investigate whether endocan could affect the concentrations of sICAM-1 and sVCAM-1 in CKD patients, particularly in those with CVD.

Design and methods

We evaluated plasma endocan, sICAM-1, sVCAM-1 and the markers of inflammation: high sensitivity C-reactive protein (hs CRP), interleukin-6, tumor necrosis factor-α (TNF-α) and their interrelationships in 53 CKD patients (both with and without CVD) and 29 healthy controls.

Results

Endocan, sICAM-1, sVCAM-1 and inflammatory markers were significantly higher in CKD patients than in controls, and patients with CVD had levels significantly higher (except interleukin-6 and TNF-α) than those without CVD. The presence of CVD, ferritin, TNF-α and SBP were the independent predictors of endocan levels in the whole CKD group. In this group, the weak relationship was between endocan and sICAM-1 and sVCAM-1, but age was the only independent predictor of these adhesion molecules. The strong association between endocan and sICAM-1 and sVCAM-1 was exclusively observed in subgroup with CVD, and the low % of lymphocytes followed by increased endocan was identified as the independent variables significantly associated with these soluble molecule levels.

Conclusions

This study shows that plasma endocan is significantly increased and independently associated with sICAM-1 and sVCAM-1 levels in CKD patients with cardiovascular complications.

Introduction

Premature atherosclerotic cardiovascular disease (CVD) is still the leading cause of increased morbidity and mortality observed in patients with chronic kidney disease (CKD) [1], [2]. Endothelial dysfunction/activation, being a key initiating step in atherogenesis, significantly contributes to the increased cardiovascular risk in patients with CKD [3], [4].

Adhesion of circulating leukocytes to the endothelium and their migration across the endothelial cells into inflammatory sites are suggested as an important step in the initiation and progression of atherosclerotic lesions [5]. This process is predominantly mediated by cellular adhesion molecules (CAMs): intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), which are expressed on the endothelial membrane in response to several inflammatory stimuli [6]. Soluble forms of these CAMs are released into the blood stream by a shedding mechanism and can be detected in the plasma [7].

Endocan, previously called endothelial cell specific molecule-1 (ESM-1), is a proteoglycan secreted by endothelial cells and can be detected in the blood [8]. The binding of circulating endocan to leukocyte ligand for ICAM-1 — Lymphocyte Function-associated Antigen-1 (LFA-1) and to leukocyte ligand for VCAM-1 — Very Late Antigen-4 (VLA-4) seems to be important in leukocyte adhesion and interaction with activated endothelium [9], [10]. Experimental and clinical data suggest that endocan is a key player in the regulation of major processes such as cell adhesion in inflammatory disorders and tumor progression [8], [9], [10], [11].

The high levels of sICAM-1 and sVCAM-1 in uraemic patients have been previously observed by us and by others, and they have been associated with carotid atherosclerosis [12], [13], [14], [15], [16], [17]. Moreover, the high soluble CAM levels were independent predictors of all cause and cardiovascular mortality in uraemia [18]. Until now, there is only one recent study describing the association between endocan and vascular abnormalities and mortality in CKD patients [19]. According to Su et al. [20], endocan is also a predictor of chronic renal allograft injury in renal transplant recipients. The aim of this study is to investigate whether an endocan-mediated pathway could affect the concentrations of sICAM-1 and sVCAM-1 in CKD patients, particularly in those with CVD. Taking into consideration the fact that the expression of endocan as well as soluble adhesion molecules are regulated by inflammatory stimuli, the markers of inflammation were also determined in these patients.

Section snippets

Subjects investigated

Fifty-three CKD patients with calculated estimated glomerular filtration rate (eGFR) 20.3 (6.2–115.0 mL/min) by simplified MDRD formula [21] were enrolled in the study. All patients were clinically stable and free of clinical signs of acute infections and autoimmune diseases. None of the patients received immunosuppressive treatment, lipid-lowering agents, non-steroidal anti-inflammatory drugs, erythropoietin or antioxidants at the time of the study. Within the whole CKD group, the presence of

Results

In the whole CKD group median endocan levels were 0.96 (0.012–5.63) ng/mL, and they were significantly higher than in controls — 0.49 (0.01–0.97) ng/mL, p < 0.001. Patients were then separated into two groups according to the presence or absence of CVD. The two groups were comparable for all demographic and clinical parameters, except higher age, lower % of lymphocytes in WBC, lower iron and higher ferritin concentrations in patients with CVD (Supplementary data).

Concentrations of endocan,

Discussion

Elevated concentrations of soluble CAMs have been documented in undialysed patients with CKD [12], [13], [14], [18], and some of them, particularly sICAM-1 and sVCAM-1, were independently associated with atherosclerosis and the prediction of death in these patients [13], [14], [18]. Endocan is a proteoglycan secreted by vascular endothelial cells and can be considered as a marker of endothelial activation [8]. Still now, there is only one study showing that plasma endocan increases in CKD

Conflicts of interest

None declared.

Acknowledgments

This work is supported by a grant No. 133-28556 provided by Medical University of Bialystok, Poland.

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Citation Excerpt :
Because of endocan’s relationship with inflammation, leukocyte adhesion and endothelial dysfunction, its role as a biomarker in CKD has been the subject of several studies. These studies consistently found significantly increased endocan concentrations in patients with CKD, when compared to controls [171-173]. Additionally, these values could translate the severity of renal disease, since higher amounts of endocan were progressively found across the different stages of CKD [171].
The vascular endothelium is localized at the interface between the blood and surrounding tissues, playing a pivotal role in the maintenance of tissue-fluid homeostasis and in the regulation of host defense, inflammation, vascular tone and remodeling, angiogenesis and haemostasis. The dysfunctional endothelium was shown to be implicated in the pathophysiology of several endothelial-dependent disorders, such as arterial hypertension, coronary artery disease, heart failure and chronic kidney disease, in which it is an early predictor of cardiovascular events.
Endocan is a soluble dermatan sulphate proteoglycan mainly secreted by the activated endothelium. It is upregulated by several proinflammatory cytokines and proangiogenic factors and may itself contribute to the inflammatory status. In addition of being a surrogate marker of inflammation and endothelial dysfunction, it seems to be involved in the regulation of several proliferative and neovascularization processes. Therefore, its utility as a biomarker in a wide spectrum of diseases has been increasingly explored.
Here, we review the current evidence concerning the role of endocan in several human cardiovascular and renal diseases, where it seems to be a promising biomarker for risk stratification, prognosis and therapeutic monitoring.
Biochemical markers of hypertension, prehypertension
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Citation Excerpt :
Lassalle et al. proposed a connection between ESM-1 and inflammatory processes, also suggesting a potential involvement of ESM-1 in vascular cell biology. Most of the researches were devoted to the study of Endocan in chronic kidney disease, diabetes, atherosclerosis [13,14]. A number of studies have shown an increase in the level of Endocan in essential hypertension, positive correlation with intima-media thickness and CRP level was noted [15].
There are insufficient researches aimed at evaluating biochemical markers of mechanisms of formation of AH and lesion of target organs in hypertension and prehypertension. The aim of that research was to study the level of endothelial dysfunction markers and damage to the cardiovascular system in hypertension and prehypertension.
A cross-sectional study was performed among 938 people aged 18 to 65 years. All respondents were surveyed, blood pressure measured, for glucose, cholesterol, interleukin-6, sFAS, LIGHT, hFABP, NT-ProBNP and an Endocan concentrations were tested. Depending on the level of blood pressure participants were splitted into groups with normotension, prehypertension and hypertension.
Comparing the markers of inflammation, apoptosis and target organ damage in the prehypertensive group, the level of the LIGHT protein was Me = 265.2 pg/ml (Q₂₅–Q₇₅: 197.7–444.3), in the control group — Me = 251.1 pg/ml (Q₂₅–Q₇₅: 176.6–376.6), the Endocan level was Me = 660.6 pg/ml (Q₂₅–Q₇₅: 419.6–867.4) and in the control group Me = 587.5 pg/ml (Q₂₅–Q₇₅: 401.9–838.1). In the AH group, the level of the LIGHT Me = 273.1 pg/ml (Q₂₅–Q₇₅: 195.1–455.2), Endocan Me = 668.2 pg/ml (Q₂₅–Q₇₅: 434.8–977.3), heart-type fatty-acid-binding protein Me = 2233.1 pg/ml (Q₂₅–Q₇₅: 1518.4–3391.1) exceeded the control group.
Thus, the development of prehypertension and hypertension is characterized by an increase in the activity of biochemical markers of endothelial dysfunction and damage to target organs, more expressed in the presence of hypertension.
Il y a des recherches insuffisantes visant à évaluer les marqueurs biochimiques des mécanismes de la formation de l’AH et la lésion des organes cibles dans l’hypertension et la préhypertension. Le but de cette recherche était d’étudier le niveau de marqueurs de la dysfonction endothéliale et les dommages au système cardiovasculaire dans l’hypertension et la préhypertension.
Une étude transversale a été réalisée auprès de 938 personnes âgées de 18 à 65 ans. Tous les répondants ont été interrogés, la pression artérielle mesurée, pour le glucose, le cholestérol, l’interleukine-6, sFAS, LIGHT, hFABP, NT-ProBNP et les concentrations d’Endocan ont été testés. Selon le niveau de pression artérielle, les participants ont été divisés en groupes avec normotension, préhypertension et hypertension.
En comparant les marqueurs de l’inflammation, de l’apoptose et des dommages aux organes cibles dans le groupe préhypertenseur, le niveau de la protéine LIGHT était Me = 265,2 pg/mL (Q₂₅–Q₇₅ : 197,7–444,3), dans le groupe contrôl — Me = 251,1 pg/mL (Q₂₅–Q₇₅ : 176,6–376,6), le taux d’Endocan était Me = 660,6 pg/mL (Q₂₅–Q₇₅ : 419,6–867,4) et dans le groupe contrôle Me = 587,5 pg/mL (Q₂₅–Q₇₅ : 401,9–838,1). Dans le groupe AH, LIGHT Me = 273,1 pg/mL (Q₂₅–Q₇₅ : 195,1–455,2), Endocan Me = 668,2 pg/mL (Q₂₅–Q₇₅ : 434,8–977,3), protéine de liaison aux acides gras de type cardiaque Me = 2233,1 pg/mL (Q₂₅–Q₇₅ : 1518,4–3391,1) a dépassé le groupe contrôle.
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View full text

Endocan — the new endothelial activation marker independently associated with soluble endothelial adhesion molecules in uraemic patients with cardiovascular disease

Highlights

Abstract

Objectives

Design and methods

Results

Conclusions

Introduction

Section snippets

Subjects investigated

Results

Discussion

Conflicts of interest

Acknowledgments

Kidney Int

Atherosclerosis

Atherosclerosis

Am Heart J

Biochem Biophys Res Commun

Biochim Biophys Acta

Am J Med Sci

Adv Med Sci

Kidney Int

Transplant Proc

Clin Biochem

Coronary artery disease in end-stage renal disease: no longer a simple plumbing problem

J Am Soc Nephrol

Endothelial dysfunction contributes to renal function-associated cardiovascular mortality in a population with mild renal insufficiency: the Hoorn study

J Am Soc Nephrol

Human endothelial-cell specific molecule-1 binds directly to the integrin CD11a/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1

J Immunol