ReviewInflammatory biomarkers for predicting cardiovascular disease
Introduction
Multiple biological pathways have been implicated in the etiology of cardiovascular disease (CVD), including, but not limited to inflammation and oxidative stress. The identification of biological markers of inflammation and oxidative stress may assist the physician in monitoring the efficacy of treatments, and facilitate the development of new pharmacological tools for patients at risk of CVD. However, due to the complexities of CVD pathogenesis there is no single biomarker available to estimate absolute risk of future cardiovascular events. Furthermore, not all biomarkers are equal; the functions of many biomarkers overlap, some offer better prognostic information than others, and some are better suited to identify/predict the pathogenesis of particular cardiovascular events. The following review provides an overview of existing and emerging biomarkers of inflammation and oxidative stress.
Section snippets
Biomarker definition
The US National Institutes of Health/Food and Drug Administration in 2001 defined a biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention [1]. The levels of an ideal biomarker should be measurable in a sample such as blood, urine, or tissue biopsy and should relate to a clinical phenotype either causally or indirectly.
Inflammatory biomarkers
Atherosclerosis, the precursor to CVD, is recognized as a chronic inflammatory disease of large arteries [2], [3]. While the process of atheroma formation has been extensively reviewed elsewhere [4], some of the relevant steps in atheromatous plaque development are briefly outlined here. Pathological studies show the abundant presence of inflammatory cells, like monocyte-derived macrophages and T-lymphocytes at the site of rupture or superficial erosion [3], [5]. These morphological
Cytokines
Most cytokines are glycoproteins that are secreted by cells using classical secretory pathways. Cytokines consist of more than 50 secreted factors involved in intercellular communication, which regulate fundamental biological processes including body growth, lactation, adiposity, and hematopoiesis [73], [136]. They are especially important for regulating inflammatory and immune responses and have crucial functions in controlling both innate and adaptive immunity. Indeed, the pathogenesis of
CD40/CD40L
CD40 ligand (CD40L) is a trimeric, transmembrane protein of the TNF family, and together with its receptor CD40 is an important contributor to the inflammatory processes that lead to atherosclerosis, plaque destabilization, and thrombosis [137], [138], [139]. A large variety of immunological and vascular cells express CD40 and/or CD40L [140]. CD40L directly regulates platelet-dependent inflammatory and thrombotic responses that contribute to the pathogenesis of atherothrombosis [141]. Both CD40
Adiponectin
Adiponectin is a protein produced by adipocytes and present at high concentration in human peripheral circulation [207], [208], [209]. Adiponectin exerts important cardiovascular functions, including anti-inflammatory, anti-apoptotic and anti-hypertrophic effects [210]. Adiponectin also controls monocyte adhesion to the vascular endothelium [211] and is an important regulator of endothelial nitric oxide synthase (eNOS) [212]. In humans, adiponectin levels appear to be closely correlated with
Chemokines
Chemokines belong to a large group of structurally related and secretable, largely basic, chemotactic cytokines [266], [267]. Chemokines are pro-inflammatory, characterized by their ability to cause directed migration of leukocytes into inflamed tissue. These chemotactic cytokines seem not only to be raised in the circulation, but also within atherosclerotic lesions [73]. Furthermore, several other leukocyte responses such as cell proliferation, enzyme secretion and induction of ROS, have been
Summary
Several chemokines have been widely investigated, including IL-8, MCP-1 and MIF. Of these, IL-8 and MCP-1 have shown particular promise as cardiac biomarkers. MCP-1 levels might serve as a direct marker of inflammatory activity for those at risk for CVD [292], and have been associated with subclinical atherosclerosis [287] and a range of CVD [154], [206], [281], [282], [288], [289], [290], [291]. IL-8 has been associated with a number of CVD [168], [189], [277], [278], [279], [280], [281], [282]
Oxidative stress
Oxidative stress results when free radical formation is unbalanced in proportion to protective antioxidants [305]. Free radicals are formed during a variety of biochemical reactions and cellular functions (such as mitochondria metabolism). Examples of free radicals (oxidizing molecules) are hydrogen peroxide, hydroxyl radical, NO, singlet oxygen, superoxide anion and peroxyl radical. Free radicals are highly reactive, unstable molecules that have an unpaired electron in their outer shell. They
Isoprostanes
Isoprostanes are cellular non-enzymatic products resulting from free radical-catalyzed peroxidation of arachidonic acid [307], [308]. In contrast to enzymatically generated prostaglandins, which are generated from free arachidonic acid, isoprostanes can be generated on intact cholesteryl esters and phospholipids, which are major components of lipoprotein particles and cell membranes. Following generation, isoprostanes are released by phospholipase activity, circulate in plasma, and are
Coenzyme Q10 (CoQ10)
CoQ10, present in all cellular membranes [363], originates from endogenous synthesis as well as from food intake and oral supplements [364]. Tissues generally synthesize CoQ10 from farnesyl diphosphate and tyrosine [365]. Iron, magnesium, and vitamin B6 are cofactors for CoQ10 biosynthesis. CoQ10 can be obtained from dietary sources of meat, fish, vegetables, and fruits. CoQ10 is an important antioxidant; its reduced form, ubiquinol, protects membrane phospholipids and mitochondrial membrane
Conclusions
Not surprisingly — due to the complexities of CVD pathogenesis — a single biomarker cannot be used to estimate absolute risk of future cardiovascular events. Furthermore, particular biomarkers are more suited for the prognosis of particular cardiovascular events, or for a given stage of a given CVD and it should also be recognized that the functions of many biomarkers overlap. For example, soluble ICAM-1 reflects in part endothelial function and in part inflammation, HSP60 might play a role
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