Oxidative Stress
Oxygen is the molecular source of the production of several molecules that damage vital tissues. Reactive oxygen and nitrogen species (RONS) are continuously produced as by-products of the reaction leading to energy production through the mitochondrial and microsomal electron-transport chains. In phagocytes, the oxidative bursts and enzyme systems such as xanthine oxidase and cytochrome P-450 oxidase are the endogenous sources of RONS. While physiological levels of RONS are crucial for cell function, excessive RONS levels trigger oxidative stress. Oxidative stress may damage clues molecules (proteins, lipids, DNA) and could, eventually, conducted to cell death. To prevent oxidative stress, antioxidants have evolved to protect biological systems against RONS-induced damage. Oxidative stress resulting from uncontrolled production of RONS that exceeds the antioxidant capacity, exacerbate atherosclerosis; since it induces endothelial dysfunction by impairing the bioactivity of endothelial NO and promotes leukocyte adhesion, enhances inflammation and thrombosis.
Numerous reports demonstrated that increased oxidative stress is associated with disturbances in cardiovascular diseases. In this sense, it was reported an overproduction of superoxide anion by cardiac dysfunctional mitochondria or increased production of RONS from non-mitochondrial sources in experimental models of type 1 diabetes (194, 195). The augmented production of RONS induces maladaptive cardiac response causing cardiac cells death contributing to cardiovascular disease (196). An excessive oxidative stress has been associated with increased cardiac cell apoptosis, as was evidenced by TUNEL+ cells and caspase 3 activation in T. cruzi-infected cardiac tissue (44). In this sense, high oxidative state has been associated with amplified lipid and DNA damage and the consequent cardiac cell injury and death. Therapeutic treatment that promotes RONS regulation have been shown to be effective in reducing cardiovascular dysfunction.
It is known that increased oxidative stress induces modifications of LDL, generating DAMPs that are detected by TLRs on different immune cell populations, mainly monocytes/macrophages. A variety of mechanisms mediated by enzymatic (such as 12/15-lipoxygenase and myeloperoxidase) or no-enzymatic redox reaction (such as RONS) boost LDL oxidation in the artery wall. The level of LDL oxidation modulates the immune system, when cells were treated with low oxLDL, the expression level of CD86, a marker for M1 macrophages, increases compared with that in cells treated with high oxLDL. In contrast, the expression level of the marker for M2 macrophages, CD206, significantly increases in cells treated with high oxLDL compared with that in cells treated with native LDL or low oxLDL. These results indicate that the degree of LDL oxidation affects the differentiation of monocytes into different subtypes of macrophages (197). Further research is needed to assess the functional consequences of oxidation processes on human macrophage behavior.