Role of TNF-alpha in vascular dysfunction

Abstract

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-alpha plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-kappaB (nuclear factor kappaB) signalling play key roles in TNF-alpha expression through an increase in circulating and/or local vascular TNF-alpha production. The increase in TNF-alpha expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-alpha expression. The interaction between TNF-alpha and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-alpha in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.

Figure 1. Pivotal role of TNF-α in vascular dysfunction

Even though numerous risk factors, such as physical inactivity, smoking and over-nutrition, appear to contribute to the development of vascular dysfunction, normal aging is also an independent factor in the aetiology of cardiovascular diseases. There is evidence, however, that those seemingly diverse processes converge on modulating TNF-α signalling to lead to the generation of dysfunctional endothelium and the onset of vascular diseases. TNF-α induces the gene expression of various inflammatory cytokines and chemokines, either dependently or independently of the activation of transcriptional factors, such as NF-κB and AP-1 (activator protein 1). This TNF-α-mediated signalling initiates and accelerates atherogenesis, thrombosis, vascular remodelling, vascular inflammation, endothelium apoptosis, vascular oxidative stress and impaired NO bioavailability, which contribute to the blunted vascular function. Dietary supplements and exercise favourably reduce the risk of vascular dysfunction by inhibiting TNF-α production and (or) TNF-α-mediated signalling. Risk factors in orange demonstrate those factors that converge on TNF-α to induce vascular dysfunction. Factors in green denote those that protect against vascular damage mediated by TNF-α expression and signalling. TNF-α-induced pathophysiological conditions related to vascular function are shown in blue. Both vascular risk factors and protective factors affect the regulation of vascular functions by modulating TNF-α production and downstream signalling. MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; TF, tissue factor.

Figure 2. Role of TNF-α in endothelial dysfunction

TNF-α reduces the production of NO through the inhibition of the enzyme activities of ASS and eNOS, and enhances the removal of NO through the increase in NADPH-dependent O₂^•− production to react with NO to form ONOO⁻. As a consequence, TNF-α decreases the bioavailability of NO to induce relaxation of smooth muscle in the vasculature. TNF-α also diminishes EETs, one of the candidate EDHFs, via the inhibition of cytochrome P450 (CYP 450) enzyme activity. AA, arachidonic acid.