Targeted increases in endothelial cell superoxide anion production stimulate eNOS-dependent nitric oxide production, not uncoupled eNOS activity.

Every once in a while a paper comes along that makes us question our understanding of cell biology. Current theory holds that oxidative stress increases oxidation of tetrahydrobiopterin (BH4), which in turn uncouples endothelial nitric oxide synthase (eNOS) activity. Numerous publications, using a variety of experimental approaches, provide strong support for the BH4 oxidation hypothesis. Indeed, nearly 10 years ago it was shown, using purified recombinant eNOS, that loss of this critical cofactor promoted eNOS generation of superoxide anion (O2 ) rather than nitric oxide ( NO) on activation.1