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Review
, 2019, 7092151
eCollection

Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease

Affiliations
Review

Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease

Sebastian Steven et al. Oxid Med Cell Longev.

Abstract

Cardiovascular disease is a leading cause of death and reduced quality of life, proven by the latest data of the Global Burden of Disease Study, and is only gaining in prevalence worldwide. Clinical trials have identified chronic inflammatory disorders as cardiovascular risks, and recent research has revealed a contribution by various inflammatory cells to vascular oxidative stress. Atherosclerosis and cardiovascular disease are closely associated with inflammation, probably due to the close interaction of inflammation with oxidative stress. Classical therapies for inflammatory disorders have demonstrated protective effects in various models of cardiovascular disease; especially established drugs with pleiotropic immunomodulatory properties have proven beneficial cardiovascular effects; normalization of oxidative stress seems to be a common feature of these therapies. The close link between inflammation and redox balance was also supported by reports on aggravated inflammatory phenotype in the absence of antioxidant defense proteins (e.g., superoxide dismutases, heme oxygenase-1, and glutathione peroxidases) or overexpression of reactive oxygen species producing enzymes (e.g., NADPH oxidases). The value of immunomodulation for the treatment of cardiovascular disease was recently supported by large-scale clinical trials demonstrating reduced cardiovascular mortality in patients with established atherosclerotic disease when treated by highly specific anti-inflammatory therapies (e.g., using monoclonal antibodies against cytokines). Modern antidiabetic cardiovascular drugs (e.g., SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 analogs) seem to share these immunomodulatory properties and display potent antioxidant effects, all of which may explain their successful lowering of cardiovascular risk.

Figures

Figure 1
Figure 1
Impact of autoimmune antibodies and inflammation markers on cardiovascular events or mortality—associations between age or glycemic state and inflammation. (a) Hazard ratios for adverse cardiovascular outcomes in correlation with autoimmune antibodies (IgG subtype) obtained by meta-analysis and adjustment for age, sex, smoking status, adiposity markers, blood pressure, and/or lipid markers (number of cases as indicated) and adjustment for classical confounders. ∗ indicates significant differences to the control group. oxLDL = oxidized low-density lipoprotein; CCP = cyclic citrullinated protein; HSP60 = heat shock protein 60. Graph was generated from tabular data by Thomson et al. [284] for anti-nitrotyrosine or Iseme et al. [18] for all other autoimmune antibodies. (b) Hazard ratios for all coronary heart disease mortality in correlation with markers of inflammation interleukin- (IL-) 6, IL-18, matrix metalloproteinase- (MMP-) 9, soluble CD40 ligand (sCD40L or CD154), and tumor necrosis factor- (TNF-) α obtained by meta-analysis and adjustment for age, sex, smoking status, adiposity markers, blood pressure, and/or lipid markers (number of cases as indicated). Risk increases are shown per 1 SD changes of cytokines. ∗ indicates significant differences to the control group. Redrawn from tabular data by Kaptoge et al. [19]. (c) Prevalence of coronary artery diseases (CAD) increases with the progressing age and gender in the general German population. Drawn from results of the DETECT study [29]. (d) Mean values of inflammatory markers (CRP = C-reactive protein and IL-6) according to the age group expressed as number of standard deviations from the sex-specific population mean to make them independent of different units of measure. Only data for men (n = 595) are shown, but those for women (n = 748) look very similar. Other markers of inflammation show similar correlations (e.g., IL-18 and fibrinogen). Graph was roughly estimated from tabular data by Ferrucci et al. [50]. (e) The correlation between HbA1c and potential risk factors. The correlation between HbA1c and body mass index (BMI), white blood cells (WBC), CRP, TNF-α, and IL-6 (n = 221 subjects). Graph was roughly estimated from graphical data by Wang et al. [62]. (f) The correlation between serum superoxide dismutase (SOD) activity, oxLDL and asymmetric dimethylarginine (ADMA) levels, and endothelial function measured by FMD (n = 59 healthy and chronic kidney disease subjects). Graph was roughly estimated from graphical data by Yilmaz et al. [117]. ∗ indicates significant differences to the control group.
Figure 2
Figure 2
Crosstalk between oxidative stress and inflammation. Interaction between ROS and mediators of inflammation exemplified by redox regulation of the transcription factors Nrf2 and NF-κB and the NLRP3 inflammasome as well as their downstream targets. In several pathways, inhibitory effects by antioxidants or genetic deletion of ROS sources are indicated. Modified from Wenzel et al. [100] (with permission from Elsevier. © 2017 Elsevier Inc.; all rights reserved).
Figure 3
Figure 3
Antioxidant, anti-inflammatory, and vasculoprotective effects by the DPP-4 inhibitor or GLP-1 analog therapy in septic rats. (a) Endothelium-dependent (ACh) relaxation was determined by isometric tension studies in rat aortic ring segments. (b) Aortic expression of inflammatory protein VCAM-1 was assessed by Western blotting analysis and specific antibodies. (c) Levels of 3-NT-positive proteins in plasma were assessed by dot blot analysis and specific antibodies. Representative blots are shown below the densitometric quantification. The data are mean ± SEM from 4-8 (a–c) rats/group. p < 0.05 vs. the control and #p < 0.05 vs. LPS. Adopted from Steven et al. [246] (with permission from Springer-Verlag Berlin Heidelberg. Copyright © 2015, Springer).
Figure 4
Figure 4
Antioxidant, anti-inflammatory, and vasculoprotective effects by the DPP-4 inhibitor or GLP-1 analog therapy in septic mice. (a) Whole blood Hb-NO levels were determined by electron paramagnetic resonance spectroscopy as a read-out of iNOS activity. (b) Mortality of endotoxemic mice was assessed by Kaplan-Meier curves recording the survival in dependence of time. 17.5 mg/kg LPS or solvent was administrated by i.p. injection. DPP-4 inhibitor (Lina: 5 mg/kg/d s.c. for 3 d) and GLP-1 analogue (Lira: 200 μg/kg/d s.c. for 3 d) treatment was started 6 h after the induction of endotoxemia. (c) Microvascular thrombosis was detected by fluorescence imaging using fluorescent microbeads in endotoxemic wild-type mice, DPP-4−/− mice, and GLP1r−/− mice. Representative images of lungs are shown beside the quantification. The data are mean ± SEM from 6-18 (a), 12 (b), or 4-6 (c) mice/group. p < 0.05 vs. B6; #p < 0.05 vs. B6+LPS; §p < 0.05 vs. GLP-1r−/−. Adopted from Steven et al. [247] (with permission from John Wiley and Sons. Copyright © 2016, John Wiley and Sons).
Figure 5
Figure 5
Antioxidant, anti-inflammatory, and vasculoprotective effects by empagliflozin therapy in ZDF rats. (a) Representative (immuno)histochemical stainings of pancreatic tissue for insulin, glucagon, and nuclei using fluorescent antibodies and dyes. (b) Improvement of endothelium-dependent relaxation by the vasodilator acetylcholine (ACh) in U46,619-preconstricted aortic ring segments. (c) Dihydroethidium (DHE, 1 μM) fluorescence microtopography was used to assess the effects of SGLT2i treatment on whole vascular wall ROS production, and representative microscope images are shown (red fluorescence indicates ROS formation whereas green fluorescence represents basal laminae autofluorescence). Linear regression analysis for correlations between HbA1c and endothelial function (ACh efficacy, d), zymosan A-induced whole blood oxidative burst (e), and serum CRP levels (f) using a total of 35-41 rats. p < 0.05 vs. the control. Adopted from Steven et al. [272] (with permission from Elsevier. © 2017 The Authors. Published by Elsevier B.V.).
Figure 6
Figure 6
Oxidative stress and inflammation trigger atherothrombosis. The scheme illustrates the activation of immune cells and recruitment to vascular tissues by classical cardiovascular risk factors, leading to the activation of secondary vascular ROS sources such as NADPH oxidase (Nox1, Nox2, and Nox4), xanthine oxidase (conversion of the dehydrogenase (XDH) to the oxidase (XO) form), mitochondria (via mitochondrial redox switches (RS)), and uncoupled eNOS (oxidative depletion of tetrahydrobiopterin (BH4) and other redox switches), all of which contribute to vascular dysfunction, progression of atherosclerosis, and thrombus formation. Adhesion molecules and chemokines (VCAM-1, ICAM-1, E-selectin, and MCP-1) play an important role for leukocyte recruitment to vascular tissues leading to the secondary damage. Endogenous antioxidant defense proteins (e.g., superoxide dismutases, glutathione peroxidases, heme oxygenase-1, and AMP-activated protein kinase) interfere with oxidative damage and redox-dependent inflammatory processes. Also, modern antidiabetic cardiovascular drugs (e.g., SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 analogs) suppress inflammatory and adverse redox pathways and thereby decrease cardiovascular risk. Modified from Steven et al. [8]. Open access article distributed under the Creative Commons Attribution License (CC BY 4.0).

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