An imbalance between the production and detoxification of ROS in vascular endothelial cells can result in the oxidative modification of cell components, impair cell function and/or can enhance cell death via apoptosis or necrosis. The oxidative activation of enzymes (e.g. phospholipase A2) and transcription factors (e.g. nuclear factor kB, NFkB) that accompanies excess ROS production can also result in an enhanced biosynthesis of lipids (e.g., platelet activating factor, leukotrienes) and proteins (adhesion molecules, cytokines) that promote inflammation. Superoxide, by virtue of its ability to inactivate nitric oxide (an anti-inflammatory molecule), is another link between oxidative stress and the induction of a pro-inflammatory phenotype in the vasculature.
There is evidence that vascular ROS production is enhanced by all of the major CV risk factors. This oxidative stress in the vessel wall is often accompanied by an increased production of superoxide anion by circulating immune cells, and there is evidence for a causal link between these two sources (circulating cells & vessel wall) of ROS. Different enzymatic sources have been implicated in the enhanced ROS production, including NADPH oxidase, xanthine oxidase, mitochondrial enzymes, and uncoupled nitric oxide synthase. A lower production of NO, which can scavenge the superoxide anion, has also been proposed as a mechanism of the enhanced ROS fluxes. [84
Many animal models of hypertension (HTN), including spontaneously hypertensive rats, chronic angiotensin II infusion and salt-retention (e.g. DOCA-salt) models, are associated with enhanced ROS production. While the elevated microvascular pressure associated with hypertension is largely confined to the arterial segment of the vascular tree, the increased oxidative stress induced by this condition is evident in both arterioles and postcapillary venules. The pathophysiological relevance of the increased ROS fluxes is evidenced by the anti-hypertensive actions of genetic SOD overexpression or SOD mimetic treatment in these models. It remains unclear whether the pro-hypertensive effects of the superoxide anion relate to its ability to inactivate NO or to indirectly promote the production of endogenous vasoconstrictors, such as endothelin. NADPH oxidase has received the most attention as a potential source of ROS in HTN, followed by xanthine oxidase. Both endothelial cell- and leukocyte-associated NADPH oxidase have been implicated in HTN-induced superoxide production, and there is evidence linking both cellular sources of the enzyme to activation of the angiotensin II type 1 receptor (AT1r) and to cytokines (TNF-alpha) derived from circulating immune cells. [16
Hypercholesterolemia (HCh) is also accompanied by increased ROS production in both arterioles and venules. This response can be completely reversed by dietary correction of the HCh. Endothelial cell denudation significantly reduces HCh-induced superoxide formation, suggesting that these cells account for most of the production. The vessel wall oxidative stress is not observed in either immunodeficient mice or in mice that are genetically deficient in interferon-γ. Since adoptive transfer of wild type T-lymphocytes into IFN-γ−/−
mice restores the oxidative stress induced by HCh, it is proposed that T-cell derived IFN-γ mediates this response. Both NADPH oxidase (endothelial cell and leukocyte) and xanthine oxidase (endothelial cell) are proposed sources of the accelerated superoxide production rates. Oxidatively modified lipoproteins (e.g., oxidized LDL), which are elevated in blood during HCh, have been implicated in different HCh-induced responses, including inflammation and eNOS uncoupling. [16
The mechanisms that contribute to the oxidative stress in obesity appear to be site specific. Vascular wall NADPH oxidase, which is presumably activated by the elevated blood levels of cytokines (adipokines) released from adipose tissue, has been implicated in the peripheral vascular oxidative stress in obese animals. However, mitochondrial uncoupling (caused by the processing of excess fatty acids) has also received much attention as a cause of the oxidative stress experienced by growing adipose tissue. The pro-oxidative environment in adipocytes that results from mitochondrial uncoupling is amplified by the enhanced ROS production that is linked to endoplasmic reticulum (ER)stress. Enhanced ROS production in adipose tissue is reflected in the accumulation of malondialdehyde and conjugated dienes, common surrogate markers of oxidative stress. [31
Hyperglycemia is widely viewed as a major stimulus for the oxidative stress associated with diabetes. Enhanced cellular uptake of glucose in insulin-independent tissues ultimately enhances oxidant production and impairs antioxidant defenses. Hyperglycemia increases superoxide production via glucose oxidase as well as NADPH oxidase, which is linked to both the generation of advanced glycosylation end-products (AGE) and protein kinase C activation. Mitochondria are the dominant site of the enhanced superoxide fluxes associated with hyperglycemia. Adiponectin, a cytokine derived from adipocytes, inhibits the increased ROS production by endothelial cells exposed to hyperglycemia via a cyclic AMP/protein kinase A pathway. [16