A molecular switch of “Yin and Yang”: S-glutathionylation of eNOS turns off NO synthesis and turns on superoxide generation

Nitric oxide (NO) is a short-lived free radical produced endogenously in biological tissues by nitric oxide synthases (NOSs)^{1, 2}. Three NOS isoforms, namely NOS1 or neuronal NOS (nNOS), NOS2 or inducible NOS (iNOS), and NOS3 or endothelial NOS (eNOS) are present in most cell types, including cardiac myocytes and vascular endothelial cells. Vascular relaxation to mediators such as acetylcholine or increased blood flow depends on NO produced by the eNOS. The discovery of NO as the endothelium-derived relaxing factor (EDRF) and its crucial function as a signaling molecule in cardiovascular system was awarded the Nobel Prize in Physiology or Medicine in 1998¹.

Under pathophysiological conditions such as hypertension, diabetes, septic shock and atherosclerosis, oxidative stress alters many functions of the endothelium and leads to endothelial dysfunction when the endothelium fails to serve its normal physiologic and protective mechanisms. A common feature of endothelial dysfunction is the reduced bioavailability of NO and increased production of superoxide (·O²⁻) and other reactive oxygen species (ROS) in the vasculature³. Multiple mechanisms may underlie the impaired NO availability⁴. These include a reduction in the expression level of eNOS mRNA or protein, changes in subcellular compartmentalization of eNOS activity, and compromised availability of the substrates and/or enzymatic cofactors for eNOS^{5, 6}. Depletion of the substrate L-arginine, accumulation of methylarginines, and oxidation of the cofactor BH₄ of eNOS can uncouple the electron transfer reactions and revert eNOS to function as an NADPH oxidase, thus producing ·O²⁻ instead of NO (Figure 1). The rapid reaction of NO with ·O²⁻ can form the most potent oxidant peroxynitrite anion (OONO⁻) and causes cellular injury associated with many pathophysiologic conditions, such as hypertension, atherosclerosis, diabetes, myocardial hypertrophy, heart failure, and ischemia/reperfusion injury⁷. The precise molecular mechanisms underlying the “switch” of the eNOS function from NO synthesis to ·O²⁻ production under oxidative stress conditions, however, are still not fully understood.

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