FIG. 4.

Prevention of vascular ROS formation and endothelial dysfunction by GTN or traffic noise exposure by pharmacological or genetic NADPH oxidase inhibition. Left part: Oxidative stress assessed by DHE staining (red fluorescence indicates reactive oxygen species [ROS] formation, whereas green fluorescence represents the autofluorescence of the basal lamina). E=Endothelium, M = Media, A = Adventitia. GTN (50 mg/kg/day for 3.5 days) treatment leads to aortic oxidative stress in rats, which was prevented by the PKC inhibitor chelerythrine (chele) (Knorr et al, 2011). Aircraft noise exposure [72 dB(A) around-the-clock for 1, 2, or 4 days] leads to aortic oxidative stress in rats, which was prevented by genetic deficiency of gp91^phox (Kroller-Schon et al, 2018). The phagocytic NADPH oxidase (NOX-2) plays a key role in the pathomechanisms underlying nitrate tolerance and noise exposure-mediated cardiovascular damage. NOX-2 is activated by ATII receptor activation, leading to DAG formation, a strong PKC activator. PKC activation can be envisaged by phosphorylation of its target protein MARCKS. Activated PKC will cause phosphorylation of p47^phox at Ser328 leading to translocation of this cytosolic regulator of NOX-2 to the multienzyme membrane complex of gp91^phox with subsequent activation of NOX-2 and superoxide formation. Right part: Endothelial dysfunction (impaired ACh-dependent relaxation) by GTN treatment was prevented in mice with genetic deficiency of p47^phox or gp91^phox (Wenzel et al, 2008). *p < 0.05 versus WT EtOH solvent control group. Endothelial dysfunction by noise exposure was prevented in mice with genetic deficiency of gp91^phox (Kroller-Schon et al, 2018). *p < 0.05 versus WT control group and ^#p < 0.05 versus gp91phox^−/− + noise group. Scheme in the left part was adapted from Frenis et al (2021c) with permission [Copyright © 2021 the authors. Open access (CC BY)]. Data in the left part were reproduced from Knorr et al (2011) (for nitrate tolerance) and Kroller-Schon et al (2018) (for noise exposure) with permission. Data in the right part were reproduced from Wenzel et al (2008) (for nitrate tolerance) and Kroller-Schon et al (2018) (for noise exposure) with permission. ACh, acetylcholine; ATII, angiotensin-II; DAG, diacylglycerol; DHE, dihydroethidine; ROS, reactive oxygen species.