Redox Regulation of Dihydrofolate Reductase

Oxidative stress is a hallmark of cardiovascular diseases1 and a major contributor to vascular dysfunction.2 On the basis on recent concepts, vascular oxidative stress is caused mainly by infiltrating inflammatory cells such as monocytes/macrophages or leucocytes,3,4 producing so-called kindling radicals that lead to the activation of secondary, vascular enzymatic sources of reactive oxygen species (mainly superoxide).2,5 A prominent example is the uncoupled nitric oxide (NO) synthase, which means that an NO-producing antiatherosclerotic enzyme is getting switched to a superoxide-producing proatherosclerotic enzyme.2 Molecular mechanisms causing endothelial NO synthase (eNOS) uncoupling or dysfunction include phosphorylation at Thr495 and Tyr657,6,7 S-glutathionylation of cysteines in the reductase domain,8 oxidative depletion of tetrahydrobiopterin (BH4),9 oxidative disruption of the zinc-sulfur dimer-binding site,10 and redox regulation of asymmetrical dimethylarginine formation and break down.2,5,11 In theory, eNOS function is also regulated …