Premium
Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling
Author(s) -
Förstermann Ulrich,
Li Huige
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01196.x
Subject(s) - enos , tetrahydrobiopterin , nicotinamide adenine dinucleotide phosphate , chemistry , superoxide , biochemistry , peroxynitrite , nitric oxide synthase , peroxynitrous acid , nadph oxidase , nitric oxide , reactive oxygen species , pharmacology , oxidase test , biology , enzyme , organic chemistry
Nitric oxide (NO) produced by the endothelium is an important protective molecule in the vasculature. It is generated by the enzyme endothelial NO synthase (eNOS). Similar to all NOS isoforms, functional eNOS transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH), via the flavins flavin adenine dinucleotide and flavin mononucleotide in the carboxy‐terminal reductase domain, to the heme in the amino‐terminal oxygenase domain. Here, the substrate L‐arginine is oxidized to L‐citrulline and NO. Cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolaemia or cigarette smoking reduce bioactive NO. These risk factors lead to an enhanced production of reactive oxygen species (ROS) in the vessel wall. NADPH oxidases represent major sources of this ROS and have been found upregulated in the presence of cardiovascular risk factors. NADPH‐oxidase‐derived superoxide avidly reacts with eNOS‐derived NO to form peroxynitrite (ONOO ‐ ). The essential NOS cofactor (6 R ‐)5,6,7,8‐tetrahydrobiopterin (BH 4 ) is highly sensitive to oxidation by this ONOO ‐ . In BH 4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting NOS to a superoxide‐producing enzyme. Among conventional drugs, compounds interfering with the renin‐angiotensin‐aldosterone system and statins can reduce vascular oxidative stress and increase bioactive NO. In recent years, we have identified a number of small molecules that have the potential to prevent eNOS uncoupling and, at the same time, enhance eNOS expression. These include the protein kinase C inhibitor midostaurin, the pentacyclic triterpenoids ursolic acid and betulinic acid, the eNOS enhancing compounds AVE9488 and AVE3085, and the polyphenolic phytoalexin trans ‐resveratrol. Such compounds enhance NO production from eNOS also under pathophysiological conditions and may thus have therapeutic potential.