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. 2023 May 3;38(13):1001–1021. doi: 10.1089/ars.2023.0006

FIG. 2.

FIG. 2.

Proposed mechanisms underlying GTN-induced and traffic noise-mediated eNOS uncoupling and diminished •NO bioavailability. Upper part: GTN treatment causes a decrease in Ser1177 (1) and an increase in Thr495 (2) phosphorylation of the eNOS (Knorr et al, 2011), leading to a decreased activity and uncoupling, respectively. In addition, the key enzyme of the de novo synthetic pathway of the eNOS cofactor BH4 GCH-1 is downregulated by chronic GTN treatment (3), also leading to a dysfunctional, superoxide (•O2−)-producing nitric oxide synthase. S-Glutathionylation represents another regulatory modification of eNOS, which is increased in the setting of tolerance (Knorr et al, 2011) and upon noise exposure (Munzel et al, 2017a; Steven et al, 2020) (4). Lower part: All of these adverse regulatory pathways that are activated by GTN treatment (50 or 100 mg/kg/day for 3.5 days) (Jabs et al, 2015; Knorr et al, 2011) or aircraft noise exposure [72 dB(A) around-the-clock for 1, 2, or 4 days] (Munzel et al, 2017a), including direct scavenging of •NO by •O2−, lead to diminished •NO bioavailability and enhanced endothelial •O2− formation that was blocked by the eNOS inhibitor L-NAME, supporting eNOS uncoupling. “?” nearby Cys689/908 means that discrimination between the S-glutathionylation sites is not possible since a pan-antibody for S-glutathionylation was used. “?” nearby BH4 means that so far rather indirect evidence exists for eNOS uncoupling via BH4 depletion by GTN tolerance and noise exposure (e.g., diminished GCH-1 and improvement of FMD by vitamin C or folic acid administration). Scheme in the upper part was reproduced from Knorr et al (2011) with permission. Images in the lower part were reproduced from Jabs et al (2015) and Knorr et al (2011) (for nitrate tolerance) and Munzel et al (2017a) (for noise exposure) with permission. Akt, protein kinase B; BH4, tetrahydrobiopterin; FAD, flavin adenine dinucleotide; FMD, flow-mediated dilation; FMN, flavin mononucleotide; GCH-1, GTP-cyclohydrolase-1; GSSG, glutathione disulfide; L-NAME, NG-nitro-l-arginine methyl ester; PKC, protein kinase C.