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. 2023 Jan 4;55(1):1–12. doi: 10.1038/s12276-022-00906-w

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Fig. 3 — eNOS uncoupling occurs due to a reduction in the eNOS cofactors arginine and BH₄ and is exacerbated by a decrease in the levels of DHFR and MTHFR, which are enzymes that regenerate BH₄ by reducing BH₂. eNOS and NOX uncoupling produces superoxide, which shows a higher affinity for NO than for its alternate scavenger, SOD, and ultimately leads to the production of OONO−, a potent oxidant. In addition to taking up NO for its own formation, OONO- oxidizes BH₄ into BH₂, reducing the eNOS cofactor. These mechanisms collaboratively decrease the NO availability during endothelial senescence. NADPH reduced nicotinamide adenine dinucleotide phosphate, NOX NADPH oxidase, eNOS endothelial nitric oxide synthase, NO nitric oxide, SOD superoxide dismutase, OONO- peroxynitrite, H₂O₂ hydrogen peroxide, H₂O dihydrogen monoxide, BH₄ tetrahydrobiopterin, BH₂ 78-dihydrobiopterin, MTHFR methylenetetrahydrofolate reductase, DHFR dihydrofolate reductase.