Endothelial Dysfunction in Chronic Inflammatory Diseases
"> Figure 1
<p>Mediators of endothelial dysfunction in inflammatory diseases. TNF-α (tumor necrosis factor-α) exerts its effects on the endothelium through its receptor, TNFR. Binding of TNFR by TNF-α leads to diminished eNOS (endothelial nitric oxide synthase) protein expression via suppression of promoter activity and destabilization of its mRNA. TNFR suppresses eNOS activity by preventing the degradation of its endogenous inhibitor, ADMA (asymmetric dimethylarginine). TNFR signaling also induces the transcription factor NF-κB leading to enhanced expression of intercellular adhesion molecules (ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1), TNF-α and Nox1 (NADPH-oxidase-1). NF-κB induction is also mediated by oxidized low density lipoprotein (oxLDL), reactive oxygen species (ROS) and binding of various autoantibodies (AECA: anti-endothelial cell antibodies; APLA: antiphospholipid antibodies; anti-oxLDL: anti-oxidized LDL antibodies). eNOS uncoupling, mediated in part by ROS, is associated with reduced NO (nitric oxide) production and enhanced generation of ROS. eNOS activity is also suppressed by oxLDL.</p> "> Figure 2
<p>From local inflammation to systemic endothelial dysfunction. TNF and inflammatory cytokines spread from the primary, disease-specific site of local inflammation into the systemic circulation to propagate a systemic inflammatory response. The byproducts of systemic inflammation, including reactive oxygen species (ROS), lipid abnormalities and other metabolic derangements are dependent on peripheral tissues such as the liver and adipose. These mediators elicit independent and complementary effects on the endothelium, leading to a state of endothelial dysfunction characterized by increased adhesion molecule expression (VCAM, ICAM), leukocyte diapedesis, ROS production and decreased NO (nitric oxide)-mediated smooth muscle relaxation and vascular dilation. Autoantibodies are generated in a disease-specific manner and induce similar changes in endothelial function.</p> ">
Abstract
:1. Introduction
2. Endothelial Dysfunction: Definitions and Prognostic Implications
3. Assessment of Endothelial Function
3.1. Forearm Blood-Flow
3.2. Flow-Mediated Vasodilation
3.3. Microvascular Vasodilation
3.4. Plasma Biomarkers of Endothelial Dysfunction
4. Clinical Findings of Major Chronic Inflammatory Diseases Suggest Cardiovascular Risk
Disease | CAD Risk (RR or OR) | Cardiovascular Mortality (RR) |
---|---|---|
Rheumatoid Arthritis | 1.5–2.0 [26,27] | 1.5 [28] |
Systemic Lupus Erythematosus | 2.2–2.6 [29,30] | 1.7 [31] |
Psoriasis (severe) | 1.5–7.1 [7,25] | 1.1–1.6 [7,25] |
Ankylosing Spondylitis | 1.9 [32,33] | 1.3–2.1 [5] |
Inflammatory Bowel Disease | 1.2–1.4 [6,34] | 1.0 [34,35] |
4.1. Rheumatoid Arthritis (RA)
4.2. Systemic Lupus Erythematosus (SLE)
4.3. The Seronegative Spondyloarthropathies and Psoriasis
4.4. Inflammatory Bowel Disease (IBD)
5. Animal Models
6. Mechanisms of Endothelial Dysfunction
6.1. Tumor Necrosis Factor-α (TNF-α)
6.2. Oxidative Stress
6.3. Dyslipidemia
6.4. Autoantibodies
7. Effects of Pharmacologic Interventions on Endothelial Function
7.1. Anti-Inflammatory Therapy
Medication | Disease(s) | Target | Effect on Endothelial Function |
---|---|---|---|
Methotrexate | RA, SpA, Psoriasis | Folic acid metabolism, lymphocyte proliferation, inflammation | Likely beneficial [2,110] |
Anti-TNF-α agents | RA, SpA, Psoriasis, IBD | TNF-α-mediated inflammation | Strong evidence for benefit [72,112,113,114,115,116,117,118,119,121] |
Corticosteroids | RA, SpA, IBD, SLE | Spectrum of immune and inflammatory responses | Inconclusive [124,125] |
Statins | RA, SLE, traditional CVD risk factors | LDL, eNOS, pleiotropic effects on inflammation | Strong evidence for benefit [126,127,128,129] |
7.2. Hydroxymethylglutaryl-CoA Reductase Inhibitors (Statins)
8. Conclusions
Acknowledgments
Conflicts of Interest
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Steyers, C.M., III; Miller, F.J., Jr. Endothelial Dysfunction in Chronic Inflammatory Diseases. Int. J. Mol. Sci. 2014, 15, 11324-11349. https://doi.org/10.3390/ijms150711324
Steyers CM III, Miller FJ Jr. Endothelial Dysfunction in Chronic Inflammatory Diseases. International Journal of Molecular Sciences. 2014; 15(7):11324-11349. https://doi.org/10.3390/ijms150711324
Chicago/Turabian StyleSteyers, Curtis M., III, and Francis J. Miller, Jr. 2014. "Endothelial Dysfunction in Chronic Inflammatory Diseases" International Journal of Molecular Sciences 15, no. 7: 11324-11349. https://doi.org/10.3390/ijms150711324