Endothelial nitric oxide synthase in vascular disease: from marvel to menace
- PMID: 16585403
- DOI: 10.1161/CIRCULATIONAHA.105.602532
Endothelial nitric oxide synthase in vascular disease: from marvel to menace
Abstract
Nitric oxide (NO*) is an important protective molecule in the vasculature, and endothelial NO* synthase (eNOS) is responsible for most of the vascular NO* produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO*. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate L-arginine, and the essential cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O2*-) reacts avidly with vascular NO* to form peroxynitrite (ONOO-). The cofactor BH4 is highly sensitive to oxidation by ONOO-. Diminished levels of BH4 promote O2*- production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH4 levels as well.
Similar articles
-
Antiatherosclerotic effects of small-molecular-weight compounds enhancing endothelial nitric-oxide synthase (eNOS) expression and preventing eNOS uncoupling.J Pharmacol Exp Ther. 2008 May;325(2):370-9. doi: 10.1124/jpet.107.128009. Epub 2008 Feb 5. J Pharmacol Exp Ther. 2008. PMID: 18252813
-
Uncoupled endothelial nitric oxide synthase and oxidative stress in a rat model of pregnancy-induced hypertension.Am J Hypertens. 2007 Dec;20(12):1297-304. doi: 10.1016/j.amjhyper.2007.08.007. Am J Hypertens. 2007. PMID: 18047920
-
Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease.Clin Sci (Lond). 2007 Jul;113(2):47-63. doi: 10.1042/CS20070108. Clin Sci (Lond). 2007. PMID: 17555404 Review.
-
Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal.Biol Chem. 2006 Dec;387(12):1521-33. doi: 10.1515/BC.2006.190. Biol Chem. 2006. PMID: 17132097 Review.
-
Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells.Cardiovasc Res. 2005 Mar 1;65(4):823-31. doi: 10.1016/j.cardiores.2004.10.040. Cardiovasc Res. 2005. PMID: 15721862
Cited by
-
Energy availability modulates regional blood flow via estrogen-independent pathways in regularly menstruating young women.Eur J Appl Physiol. 2024 May 29. doi: 10.1007/s00421-024-05497-0. Online ahead of print. Eur J Appl Physiol. 2024. PMID: 38809480
-
Increased Prolylcarboxypeptidase Expression Can Serve as a Biomarker of Senescence in Culture.Molecules. 2024 May 9;29(10):2219. doi: 10.3390/molecules29102219. Molecules. 2024. PMID: 38792081 Free PMC article.
-
Evaluation of CSF 8-iso-prostaglandin F2α and erythrocyte anisocytosis as prognostic biomarkers for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.Sci Rep. 2024 May 17;14(1):11302. doi: 10.1038/s41598-024-61956-w. Sci Rep. 2024. PMID: 38760404 Free PMC article.
-
Deletion of Sigmar1 leads to increased arterial stiffness and altered mitochondrial respiration resulting in vascular dysfunction.Front Physiol. 2024 Apr 29;15:1386296. doi: 10.3389/fphys.2024.1386296. eCollection 2024. Front Physiol. 2024. PMID: 38742156 Free PMC article.
-
Endothelial Dysfunction in Heart Failure: What Is Its Role?J Clin Med. 2024 Apr 25;13(9):2534. doi: 10.3390/jcm13092534. J Clin Med. 2024. PMID: 38731063 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical