Oxidative Medicine and Cellular Longevity / 2019 / Article / Tab 1

Review Article

Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease

Table 1

Molecular proof for a crosstalk between oxidative stress and inflammation in mice or cell culture with genetic modulation of antioxidant defense or ROS-producing enzymes.

Antioxidant or prooxidant proteinPhenotypic changesReference

Glutathione peroxidase-1 (GPx-1), homozygous deficiency(1) Increased marker of inflammation (CD68 and F4/80 staining) and increased vascular and mitochondrial ROS formation (dihydroethidine (DHE) staining)
(2) Increased cardiac and vascular NOX-2 activity
(3) Vascular dysfunction and eNOS uncoupling
(4) Age-dependent progressive phenotype of low-grade inflammation, impaired redox balance, and vascular dysfunction
(5) Increased adhesion of leukocytes to cultured GPx-1-deficient endothelial cells
[46, 143]

GPx-1 deficiency in human microvascular endothelial cells (HMVEC)(1) Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression via ROS and NF-κB
(2) More TNF-alpha-induced ROS production and activation of ERK1/2 and JNK (that was suppressed by GPx-1 overexpression)

GPx-1/2 deficiency, homozygous double knockout(1) Loss of control of inflammatory response in the intestinal mucosa
(2) Symptoms and pathology consistent with inflammatory bowel disease (colitis)
(3) High incidence of mucosal inflammation in the ileum and colon
(4) Elevated levels of myeloperoxidase activity and lipid hydroperoxides in the colon mucosa

Mitochondrial superoxide dismutase (Mn-SOD or SOD2), heterozygous deficiency(1) Higher NOX-2 activity in isolated white blood cells
(2) Endothelial dysfunction
(3) Further aggravation of endothelial dysfunction, eNOS uncoupling, and hypertension upon challenges with AT-II

Cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD and SOD1) homozygous and heterozygous deficiency(1) More pronounced cognitive impairment and synaptic dysfunction in the Alzheimer disease model
(2) Increased amyloid β (Aβ) 40/42 oligomers plaque formation in the brain
(3) Increased neuronal inflammation by activation of microglia and astrocytes
(4) Increased cerebral oxidative damage (measured by 8-oxo-dG)

Extracellular superoxide dismutase 3 (SOD3), homozygous deficiency and overexpression(1) Deficiency aggravated ovalbumin-induced allergic airway inflammation in mice as a model of asthma
(2) Deficiency increased infiltrated leukocytes and cytokine levels in lung tissue
(3) Overexpression decreased inflammatory molecules in lung fibroblasts (chemokine receptor 4 (CCR4), TNF-α, TGFβ, IL-1α, and IL-1β)
(4) Overexpression reduced extracellular matrix molecules (collagen III and syndecan1)

Heme oxygenase-1 (HO-1), homozygous and heterozygous deficiency(1) Induction of NOX-2 at the protein level ()
(2) More vascular ROS and endothelial dysfunction
(3) Further aggravation upon challenges with AT-II
(4) Increased expression of the C-C chemokine receptor type 2 (CCR2 or CD192)
(5) More pronounced leukocyte rolling and adhesion to the endothelial cell layer
(6) Increased numbers of infiltrated neutrophils and monocytes in aortic tissue
(7) Further aggravation of endothelial dysfunction in the setting of diabetes and during the aging process

Endothelial and myelomonocyte-specific α1AMPK deficiency (TekCre and LysMCre mice)(1) Adverse AT-II effects (endothelial dysfunction and oxidative stress, markers of inflammation and leukocyte rolling/adhesion/infiltration) were further aggravated in
(2) Adverse AT-II effects (endothelial dysfunction and oxidative stress, markers of inflammation and leukocyte rolling/adhesion/infiltration) were further aggravated in in a HO-1-dependent manner
(3) α1AMPK and HO-1 siRNA caused increased expression of VCAM-1 and MCP-1 in cultured endothelial cells, all of which were rescued by treatment with PEG-SOD
[279, 280]

Endothelial cell-specific Nox2 transgenic overexpression(1) Greater cardiac fibrosis
(2) More pronounced left ventricular diastolic dysfunction
(3) More inflammatory cells (CD45+ and MAC3+) and VCAM-1-positive vessels in the myocardium upon challenges with AT-II
(4) Increased adhesion of leukocytes to cultured endothelial cells of Nox2 transgenic mice upon challenges with AT-II

Nox2, homozygous deficiency(1) Protection against aircraft noise-induced endothelial dysfunction and vascular/cerebral oxidative stress
(2) Prevention of aircraft noise-induced increases in plasma IL-6 or cerebral iNOS, CD68, and IL-6 levels

Nox1, homozygous deficiency(1) Less diethylnitrosamine- (DEN-) induced liver tumors
(2) Decreased TNF-α and IL-6 levels upon DEN challenges
(3) Protective effects were also seen in macrophage-specific Nox1-deficient mice (but not in those mice with hepatocyte- or hepatic stellate cell-specific Nox1 deficiency or global Nox4-/- mice)

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