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 protein	Phenotypic changes	Reference
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)	[275]
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	[276]
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	[78]
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)	[277]
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)	[278]
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	[222]
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	[281]
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	[282]
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)	[283]