Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling
- 22 August 2011
- journal article
- review article
- Published by Wiley in British Journal of Pharmacology
- Vol. 164 (2), 213-223
- https://doi.org/10.1111/j.1476-5381.2010.01196.x
Abstract
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 (6R-)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.Keywords
This publication has 114 references indexed in Scilit:
- Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathyNephrology Dialysis Transplantation, 2008
- Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitusAtherosclerosis, 2008
- SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthaseProceedings of the National Academy of Sciences of the United States of America, 2007
- Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted miceCardiovascular Research, 2007
- Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapyProceedings of the National Academy of Sciences of the United States of America, 2006
- Therapeutic potential of resveratrol: the in vivo evidenceNature Reviews Drug Discovery, 2006
- PLEIOTROPIC EFFECTS OF STATINSAnnual Review of Pharmacology and Toxicology, 2005
- Upregulation of Vascular NAD(P)H Oxidase Subunit gp91phox and Impairment of the Nitric Oxide Signal Transduction Pathway in HypertensionBiochemical and Biophysical Research Communications, 2001
- Oxidation of Tetrahydrobiopterin by Peroxynitrite: Implications for Vascular Endothelial FunctionBiochemical and Biophysical Research Communications, 1999
- Interferon-γ inhibits proliferation of rat vascular smooth muscle cells by nitric oxide generationBiochemical and Biophysical Research Communications, 1992