Plasma markers of endothelial dysfunction in type 2 diabetics

doi:10.1016/j.ejim.2005.09.015

European Journal of Internal Medicine

Volume 17, Issue 1, January 2006, Pages 38-42

https://doi.org/10.1016/j.ejim.2005.09.015 Get rights and content

Abstract

Background

Type 2 diabetes, or non-insulin-dependent diabetes mellitus, represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continuous low-grade inflammation and endothelial activation state. Atherosclerotic lesions occur in diabetic patients at an earlier age with severe clinical manifestations and poor outcome. Our objective was to investigate the correlation between lipoprotein-associated phospholipase A₂ (PLA₂-LDL), myeloperoxidase (MPO), and paraoxonase (PON), enzymes implicated in the evolution of endothelial dysfunction associated with type 2 diabetes.

Methods

One hundred diabetic patients [50 without documented coronary artery disease (group 1) and 50 with CVD (group 2)] and 46 healthy controls were investigated for PLA₂-LDL, MPO, and PON activities.

Results

PLA2-LDL activity was significantly higher in group 2 than in group 1 and among controls. PON activity was lower in group 1 than in controls, reaching the lowest level in group 2. MPO activity was higher in type 2 diabetics than among controls, with similar values in groups 1 and 2.

Conclusions

The evaluation of PLA2-LDL, MPO, and PON activities may improve early diagnosis of CVD in asymptomatic patients with type 2 diabetes and can help to evaluate accelerated atherosclerosis and microvascular disease.

Introduction

Type 2 diabetes, or non-insulin-dependent diabetes mellitus, represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continuous low-grade inflammation and endothelial activation state [1], [2]. Numerous prospective cohort studies have indicated that type 2 diabetes is associated with a three- to fourfold increase in risk for CVD [3], [4], [5], [6].

Type 2 diabetes, like other traditional risk factors, determines an abnormal endothelium response that is thought to precede the development of atherosclerosis because endothelium dysfunction can be detected before angiographic evidence of atherosclerotic lesions becomes detectable [7]. Hsueh et al. have suggested that abnormal endothelial function precedes other evidence of vascular disease and that the progression of insulin resistance to type 2 diabetes parallels the progression of endothelial dysfunction to atherosclerosis. Moreover, they suggest that reducing the progression of endothelial dysfunction to atherosclerosis also attenuates the progression of insulin resistance to type 2 diabetes [8].

Our published data have shown that plasma platelet-activating factor-acetylhydrolase, also known as lipoprotein-associated phospholipase A₂ (PLA₂-LDL), is a risk marker for endothelial dysfunction in patients with type 2 diabetes [9]. PLA₂-LDL is a Ca²⁺ -independent phospholipase A₂ that hydrolyzes and inactivates platelet-activating factors and phospholipids containing oxidative fragmented residues at the sn-2 position formed during oxidative modification of LDL [10]. PLA₂-LDL-mediated production of lysophosphatidilcoline (LPC) represents a proatherogenic mechanism because LPC mediates numerous atherogenic effects, including up-regulation of endothelial cell surface P-selectin expression [11], [12].

The West of Scotland study group reported that baseline levels of PLA₂-LDL were a strong, independent predictor for incidental coronary heart disease in a cohort of high-risk hyperlipidemic men. The patients with the highest levels of PLA₂-LDL had twice the risk of a cardiovascular event compared to those with the lowest level [13]. Elevated PLA₂-LDL has also been associated with an increased risk of cardiovascular events in women [14]. PLA₂-LDL activity reflects the ongoing inflammatory process and may predict risk in patients with coronary artery disease (CAD) [15].

Myeloperoxidase (MPO) is another enzyme that plays an active role in the induction and evolution of endothelial dysfunction. MPO is a bactericidal enzyme secreted by neutrophils, monocytes, and certain tissue macrophages, including those found in atherosclerotic plaques. MPO specifically catalyzes the production of hypoclorous (a compound mediating a number of potentially deleterious reactions) from chloride and hydrogen peroxide [16]. The enzyme is released by degranulation of activated leukocytes [17].

MPO is implicated in LDL oxidation in vivo, transforming these lipoproteins into a high-uptake form for macrophages, leading to cholesterol deposition and foam cell formation [18]. According to Zouaoui Boudjeltia et al., the oxidation of LDL in situ is not restricted to the subendothelial space; this process may also occur at the surface of the endothelial cells [19]. MPO also uses nitric oxide as a physiologic substrate, contributing in this way to endothelial dysfunction [20]. Both enzymes, PLA₂-LDL and MPO, are considered to be inflammatory markers related to coronary disease [21].

Paraoxonase (PON) [aryldialkylphosphatase (EC 3.1.8.1)], an HDL-associated enzyme, protects LDL from oxidative damage, having a direct protective effect against CVD [22]. PON has the capacity to reduce the accumulation of oxidized phospholipids in the blood of hyperlipidemic people [23].

We were interested in investigating the correlation between PLA₂-LDL, MPO, and PON, enzymes correlated with the inflammatory state existing in type 2 diabetes, because these enzymes are implicated in the evolution of endothelial dysfunction. In addition, the evaluation of the activity of these enzymes may improve the early diagnosis of CVD in diabetic patients, which is usually diagnosed at an advanced stage [24].

Section snippets

Methods

The study included 100 diabetic patients and 46 healthy controls, age- and gender-matched. Diabetic patients were divided into two groups: group 1, consisting of 50 patients without documented CVD, and group 2, consisting of 50 patients with chronic stable angina and documented previous CVD (Table 1).

Patients with recent cardiovascular events [acute coronary syndromes, stroke, and acute or severe peripheral artery disease (ankle brachial index < 0.7)] were excluded from the study.

Patients

Results

The PLA₂-LDL activities were significantly higher [mean (SD) 400.1 (92.58)] in patients with type 2 diabetes and CVD (group 2) than in healthy subjects [(mean (SD) 210.8 (19.49)] and patients with type 2 diabetes without CVD (group 1) [mean (SD) 309.97 (31.74)] (Table 2).

PON activity in the control group was distributed between 62.9 and 112.6 U [(mean (SD) 86.21 (13.1)]. PON activity was lower in diabetics than in controls: group 1 [(mean (SD) 51.4 (13.31)] and group 2 [(mean (SD) 40.02

Discussion

Diabetic patients have generally been described as being under enhanced oxidative stress. Hyperglycemia increases intracellular oxidative stress and causes glycosylation of proteins and aminophospholipids. Early reaction products (glucose-derived Schiff base, Amadori products) undergo a series of inter- and intramolecular rearrangement, dehydration, and oxidation–reduction reactions to produce advanced glycation end-products (AGEs). Activation of phagocytes through a specialized receptor for

Acknowledgements

The present study was supported by the National Research Program Viasan, under the patronage of the Romanian Academy of Medical Science, Grant 240/2003.

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Original articlePlasma markers of endothelial dysfunction in type 2 diabetics

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

Med Clin North Am

Am J Med

Atherosclerosis

J Am Coll Cardiol

Eur J Med

J Biol Chem

Biochem Biophys Res Commun

J Lipid Res

Diabetes Res Clin Pract

Clin Chim Acta

Diabetes Res Clin Pract

Clin Biochem

Biochem Biophys Res Commun

Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association

Circulation

Diabetes and atherogenesis

Heart

Diabetes and cardiovascular disease. The Framingham study

JAMA

Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction

N Engl J Med

Original article
Plasma markers of endothelial dysfunction in type 2 diabetics