Abstract
Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The general concept of redox-based activation of RONS sources via “kindling radicals” and enzyme-specific “redox switches” as well as the interaction with redox-sensitive inflammatory pathways are discussed. Here, we present evidence for the existence of such cross talk mechanisms in the setting of diabetes and critically assess their contribution to the severity of diabetic complications.
Highlights
The degradation product of O2 ̄, hydrogen peroxide (H2O2), may confer redox signaling by oxidation of protein thiol groups and act as an important second messenger that is essentially involved in fundamental cellular processes such as eustress [2,3] or cell differentiation/proliferation [4], its concentrations need to be tightly controlled by catalase and glutathione peroxidases (GPx) to prevent oxidative stress conditions and exaggerated oxidative damage of cellular structures [5]
Redox signaling may become an attractive target for drug development in the future, but its complexity warrants in-depth mechanistic understanding and careful fine-tuning since ROS are by-products causing damage and fulfill essential physiological signaling functions [11]
The fact that this cross talk is not limited to the interplay of different ROS sources but can be extended to interactions of ROS with inflammatory pathways, advanced glycation end products (AGEs)/RAGE signaling, vasoconstrictor synthesis, thrombosis/coagulation, and very clearly endothelial function (Figure 6), makes therapeutic targeting complicated
Summary
A molecular proof of the existence of superoxide anion radical (O2 ̄) formation in the organism was based on the discovery of superoxide dismutases (SODs, mitochondrial Mn-SOD, and cytosolic/extracellular Cu,Zn-SOD) in living organisms by Fridovich and coworkers in the 1960s [1]. The oxidative degradation of NO by O2 ̄ directly contributes to endothelial dysfunction by removal of a potent vasodilator. The formation of ONOOcauses oxidative damage of important vascular proteins, e.g., endothelial nitric oxide synthase (eNOS) [45,46], sGC [47], and prostacyclin synthase (PGIS) [48] and thereby contributes to endothelial (vascular) dysfunction [49,50]. The interplay and steady-state levels of O2 ̄, NO, and their reaction product ONOOas well as their tight control by antioxidant enzymes largely determine cellular redox state and whether RONS at low concentrations act as messengers in redox signaling or at high concentrations cause oxidative stress and damage of biomolecules (Figure 2) [11].
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