Title:Molecular Mechanisms of Endothelial NO Synthase Uncoupling
Volume: 20
Issue: 22
Author(s): Suxin Luo, Han Lei, Honghua Qin and Yong Xia
Affiliation:
Keywords:
NO, endothelial NO synthase, superoxide, tetrahydrobiopterin, uncoupling.
Abstract: Nitric oxide (NO) is a gaseous signaling molecule and effector in various biological processes. In mammalian cells, NO is
produced by a family of NO synthases (NOS). Three NOS isoforms have been identified as: neuronal NOS (nNOS), inducible NOS
(iNOS), and endothelial NOS (eNOS). In addition to NO, NOS also produces superoxide anion. This phenomenon is named NOS uncoupling
as superoxide generation mainly occurs when NOS is not coupled with its cofactor or substrate. nNOS was first found to produce
superoxide under L-arginine depletion condition. Further studies demonstrated that superoxide production is a general feature of all three
NOS isoforms. In particular, superoxide generated from uncoupled eNOS has been found to play critical roles in the process of various
cardiovascular diseases. Although NOS was first found to produce superoxide only when uncoupled with its cofactor or substrate, recent studies
reveal that oxygen reduction to superoxide is an intrinsic process amid NO synthesis. Tetrahydrobiopterin plays a controlling role in preventing
superoxide release from the eNOS oxygenase domain. Besides tetrahydrobiopterin, the regulation of eNOS uncoupling by the interactions
with other proteins, protein phosphorylation, S-glutathionylation, and endogenous L-arginine derivatives, will be discussed in this
review.
