Antioxidants, inflammation and cardiovascular disease

Abstract

Multiple factors are involved in the etiology of cardiovascular disease (CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells, leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species (ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or, and even more likely, due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress, however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover, molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signaling pathways involved in the regulation of immunological, metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response, interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, fibroblasts, endothelial and epithelial cells. Neopterin, a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase I in macrophages and dendritic cells. Nitric oxide synthase (NOS) is induced in several cell types to generate nitric oxide (NO). NO, despite its low reactivity, is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin (BH4), which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite (ONOO(-)) is formed solely in the presence of superoxide anion (O2 (-)). Neopterin and kynurenine to tryptophan ratio (Kyn/Trp), as an estimate of IDO enzyme activity, are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise, a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C, -E and -B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites, BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.

Keywords: Antioxidative therapy; Atherogenesis; Cardiovascular disease; Homocysteine; Neopterin; Nitric oxide; Oxidative stress; Tetrahydrobiopterin; Tryptophan; Vitamins.

Figures

Figure 1

Regulatory circuits in inflammation and endothelial dysfunction. During inflammation, NADPH oxidase (NOX) produces high levels of reactive oxygen species (ROS). T cells and natural killer cells produce interferon-γ, which activates enzyme GTP-cyclohydrolase I (GTP-CH-I), indoleamine 2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS) in monocyte-derived macrophages (M) and dendritic cells (DC). In endothelial cells, endothelial NOS (eNOS) is constitutively expressed and GTP-CH-I produces tetrahydrobioterin (BH4), which is a NOS cofactor. BH4 deficiency leads to NOS uncoupling and superoxide anion (O2-) formation, which reacts with NO to form peroxynitrite (ONOO-). In a vicious cycle, ONOO- oxidizes BH4. In M/DC, GTP-CH-I synthesizes neopterin at expense of BH4, which contributes to the low activity of iNOS in human M/DC. Furthermore, NO is a reversible inhibitor of the immunoregulatory enzyme IDO. IDO degrades the essential amino acid tryptophan to kynurenine.

Figure 2

Dysregulation of redox- and Th1/Th2-balance in the course of atherogenesis. Excessive antioxidant intake in combination with other risk factors such as high caloric diet and low physical exercise lead to suppression of Th1-type immunity, thereby favoring Th2-associated development of allergies and asthma and promoting juvenile obesity. Factors such as high blood pressure and hyperlipidemia lead to shear stress and tissue injury. Inflammatory reactions are associated with high reactive oxygen species generation, which results in immunotoxicity due to oxidation of biomolecules (lipids, proteins, etc.).