title: Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid.
abstract: It has been shown that endothelial NO synthase (eNOS) uncoupling occurs in hypertension and atherosclerosis. However, its causal role in vascular pathogenesis has not been characterized previously. Here, we challenged eNOS preuncoupled hyperphenylalaninemia (hph)-1 mice (deficient in eNOS cofactor tetrahydrobiopterin biosynthetic enzyme GTPCHI) with angiotensin II (Ang II; 0.7 mg/kg per day, 14 days). Both wild-type and hph-1 groups developed hypertension similarly up to day 6 to 7. Thereafter, ≈14% of Ang II-infused (0.7 mg/kg per day) hph-1 mice (n=72) started to die suddenly of ruptured abdominal aortic aneurysm (AAA). Among the survivors, 65% developed AAA, resulting in a total morbidity rate of 79%. In contrast, none of the Ang II-infused wild-type mice died or developed AAA. Ang II progressively deteriorated eNOS uncoupling in hph-1 mice while augmenting tetrahydrobiopterin and nitric oxide (NO(·)) deficiencies. The abundance of the tetrahydrobiopterin salvage enzyme dihydrofolate reductase in the endothelium was decreased in hph-1 mice and further diminished by Ang II infusion. Intriguingly, restoration of dihydrofolate reductase expression by oral administration of folic acid or overexpression of dihydrofolate reductase completely prevented AAA formation in Ang II-infused hph-1 mice while attenuating progressive uncoupling of eNOS. Folic acid also attenuated vascular remodeling and inflammation characterized by medial elastin breakdown and augmented matrix metalloproteinase 2 activity and activation of matrix metalloproteinase 9, as well as macrophage infiltration. In conclusion, these data innovatively suggest a causal role of eNOS uncoupling/tetrahydrobiopterin deficiency in AAA formation. Therefore, oral folic acid administration, endothelium-targeted dihydrofolate reductase gene therapy, and perhaps other countermeasures directed against eNOS uncoupling could be used as new therapeutics for AAA.
authors.affiliation: Division of Molecular Medicine, Cardiovascular Research Laboratories, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, 650 Charles E Young Dr, Los Angeles, CA 90095, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Kin L
authors.initials: KL
authors.lastname: Siu
authors.forename: Karel
authors.initials: K
authors.lastname: Chalupsky
authors.forename: Andrew
authors.initials: A
authors.lastname: Nguyen
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.forename: Zorina
authors.initials: Z
authors.lastname: Galis
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D001019:Aortic Rupture / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005492:Folic Acid / Q000494:pharmacology*; D006136:GTP Cyclohydrolase / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D014803:Vitamin B Complex; D001708:Biopterins; D009569:Nitric Oxide; D005492:Folic Acid; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013762:Tetrahydrofolate Dehydrogenase; D006136:GTP Cyclohydrolase; C003402:sapropterin
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