6533b826fe1ef96bd1283f36
RESEARCH PRODUCT
Prevention of Atherosclerosis by Interference with the Vascular Nitric Oxide System
Huige LiUlrich Förstermannsubject
medicine.medical_specialtySepiapterinNitric Oxide Synthase Type IIImedicine.drug_classGTP cyclohydrolase INitric Oxidemedicine.disease_causeRenin inhibitorNitric oxidechemistry.chemical_compoundEnosInternal medicineDrug DiscoverymedicineAnimalsHumansHypolipidemic AgentsPharmacologybiologyArteriesTetrahydrobiopterinAtherosclerosisbiology.organism_classificationNitric oxide synthaseOxidative StressTreatment OutcomeEndocrinologychemistrybiology.proteinOxidative stressSignal Transductionmedicine.drugdescription
Nitric oxide (NO) produced by endothelial NO synthase (eNOS) represents an anti-atherosclerotic principle. NO bioavailability is decreased in atherosclerosis due to increased NO inactivation by reactive oxygen species and reduced NO synthesis. Various types of vascular pathophysiology are associated with oxidative stress, with NADPH oxidases as the major source of reactive oxygen species. These inactivate NO. Also, oxidative stress is likely to be the main cause for oxidation of the essential NOS cofactor, tetrahydrobiopterin (BH(4)). A lack of BH(4) leads to eNOS uncoupling (i.e., uncoupling of oxygen reduction from NO synthesis in eNOS). Based on these pathomechanisms, the therapeutic potential of a number of compounds is discussed in this review: (1) NO donors; (2) L-arginine; (3) folic acid; (4) BH(4) and its precursor sepiapterin; (5) compounds that upregulate eNOS and concomitantly maintain eNOS activity (e.g. midostaurin, betulinic acid, ursolic acid, AVE9488 and AVE3085); (6) compounds that enhance the de novo synthesis of BH(4) by stimulating expression or activity of GTP cyclohydrolase I; and (7) 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins) and drugs interrupting the renin-angiotensin-aldosterone system. Statins, angiotensin II type 1 receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, the aldosterone antagonist eplerenone and the renin inhibitor aliskiren enhance NO bioactivity and reduce atherosclerosis progression through multiple mechanisms.
year | journal | country | edition | language |
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2009-09-17 | Current Pharmaceutical Design |