Review
Is exercise training an effective therapy targeting endothelial dysfunction and vascular wall inflammation?

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Abstract

There is an increasing evidence that endothelial dysfunction and vascular wall inflammation are present in all stages of atherosclerosis. Atherosclerosis does not have to necessarily progress to an acute clinical event. Several therapeutic strategies exist, such as exercise training, which mitigates endothelial dysfunction and inflammation. Exercise training consistently improves the nitric oxide bioavailability, and the number of endothelial progenitor cells, and also diminishes the level of inflammatory markers, namely pro-inflammatory cytokines and C-reactive protein. However, the mechanisms by which exercise improves endothelial function in coronary artery disease patients are not fully clarified. Several mechanisms have been proposed to explain the positive effect of exercise on the disease progression. They include the decrease in cytokine production by the adipose tissue, skeletal muscles, endothelial cells, and blood mononuclear cells, and also, the increase in the bioavailability of nitric oxide, antioxidant defences, and regenerative capacity of endothelium. This study aims to provide a critical review of the literature linking exercise, inflammation, and endothelial dysfunction in coronary artery patients, and to discuss the potential mechanisms behind the exercise-training improvement of endothelial function and inflammatory status.

Introduction

Coronary artery disease (CAD) remains the main cause of mortality in developed countries [1], [2]. CAD results from the development of atherosclerosis in one or more coronary arteries [3]. In the last decades the understanding of the pathogenesis of atherosclerosis has dramatically changed. Atherosclerosis is no longer seen as a bland lipid storage disease; currently, atherosclerosis is considered a dynamic and gradual process of endothelial dysfunction and chronic low-level inflammation [4], [5], [6]. This process involves cells of the vascular wall, monocytes, T-lymphocytes, pro-inflammatory cytokines, chemokines and growth factors, which stimulate the acute phase proteins production, causing damage and ultimately plaque rupture [4], [5], [6], [7]. Several of these molecules, reflecting the endothelial function and inflammation, have been investigated and studying their levels has been found as a way to predict cardiovascular risk in a variety of clinical settings [8]. The understanding that endothelial dysfunction and vascular wall inflammation play a key role in the atherogenesis and in the stability of the established plaques provides insight into novel therapeutic targets [4], [5], [9], [10]. Thus, endothelial dysfunction and inflammation become promising targets for both primary and secondary prevention of CAD. Among the intervention strategies, exercise training has emerged as an effective non-pharmacological tool.

Exercise training is an established therapeutic intervention with several benefits, including the modification of numerous traditional risk factors, the enhancement of exercise tolerance, the enhancement of myocardial and peripheral perfusion, and most importantly the reduction of morbidity and mortality in patients with CAD [11], [12]. However, the basic mechanisms behind this positive impact are not fully understood. Several studies [13], [14], [15], [16], [17] have recently highlighted the important role of exercise in the mitigation of endothelial dysfunction and vascular inflammation, giving rise to a new set of potential explanations for the beneficial outcomes of regular exercise in CAD patients. Thus, the purpose of this study is to provide a critical review of the literature linking exercise, inflammation, and endothelial dysfunction in CAD patients, and to discuss the potential mechanisms underlying the exercise-training improvement of endothelial function and inflammatory status.

Section snippets

Coronary artery disease, endothelial dysfunction and inflammation

The pathophysiology of CAD has been subject of several valuable reviews [4], [5], [6], [7], [18]. Recent research has shown that endothelial dysfunction and low-grade vascular inflammation play a key role in CAD and other manifestations of atherosclerosis. The development of the atherosclerotic plaque begins with a focal endothelial cell dysfunction [4], [5]. This includes the overexpression of cellular adhesion molecules, which promote the recruitment of blood mononuclear cells, and the

Exercise and endothelial dysfunction

Endothelial cell integrity is essential for preserving vascular homeostasis, allowing the continuous adjustment of vascular tone, the physiological regulation of leukocyte traffic, and the maintenance of blood fluidity [21]. In several pathological conditions, such as in atherosclerosis, the endothelial function is chronically disturbed in local areas. Endothelial dysfunction is characterized by an alteration in the basal endothelial phenotype (vasorelaxant, anticoagulant, antiplatelet and

Exercise and biomarkers of inflammation

The anti-inflammatory effect of exercise training in CAD patients has been assessed through the measurement of circulating levels of systemic biomarkers of inflammation, namely circulating cytokines and CRP.

Cytokines are a group of proteins with relatively small molecular weights [83]. The pathogenesis of atherosclerosis involves several cytokines from the interleukin group (for instance IL-1, -4, -6, -8, -10) and macrophage associated cytokines such as TNF-α, interferon (IFN)-γ and colony

Summary

Current research seems to indicate that exercise training is an effective therapeutic modality for mitigating endothelial dysfunction and vascular wall inflammation. These positive effects of chronic exercise could be explained by several mechanisms including: the augment of the bioavailability of ˙NO and antioxidant defences, the decrease in pro-inflammatory cytokines production by the adipose tissue, skeletal muscles, endothelial cells, blood mononuclear cells, and, the increase of the

Review criteria

The authors conducted a PubMed search to identify English-language articles published up to January 2009. The searching terms were: coronary artery disease and exercise training in sequence with the terms C-reactive protein, inflammation, endothelial dysfunction, inflammatory biomarkers, cytokines, nitric oxide, endothelial progenitor cells, or cellular adhesion molecules. The cited papers were selected on the basis of their relevance with the topic of this review. Reference lists in the

Acknowledgments

“The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology” [109].

This work was supported by Fundação para a Ciência e Tecnologia (FCT) Grant SFRH/BD/15843/2005 (to Fernando Ribeiro).

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