Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: Treatment with folic acid

Ling Gao, Kin L. Siu, Karel Chalupsky, Andrew Nguyen, Peng Chen, Neal Lee Weintraub, Zorina Galis, Hua Cai

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)158-166
Number of pages9
JournalHypertension
Volume59
Issue number1
DOIs
StatePublished - Jan 1 2012

Fingerprint

Phenylketonurias
Nitric Oxide Synthase Type III
Abdominal Aortic Aneurysm
Folic Acid
Nitric Oxide Synthase
Tetrahydrofolate Dehydrogenase
Therapeutics
Endothelium
Hypertension
Aortic Rupture
Elastin
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Enzymes
Angiotensin II
Genetic Therapy
Blood Vessels
Oral Administration
Survivors
Atherosclerosis

Keywords

  • abdominal aortic aneurysm, eNOS uncoupling
  • folic acid, dihydrofolate reductase
  • hph-1 mice
  • tetrahydrobiopterin, angiotensin II

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation : Treatment with folic acid. / Gao, Ling; Siu, Kin L.; Chalupsky, Karel; Nguyen, Andrew; Chen, Peng; Weintraub, Neal Lee; Galis, Zorina; Cai, Hua.

In: Hypertension, Vol. 59, No. 1, 01.01.2012, p. 158-166.

Research output: Contribution to journalArticle

Gao, Ling ; Siu, Kin L. ; Chalupsky, Karel ; Nguyen, Andrew ; Chen, Peng ; Weintraub, Neal Lee ; Galis, Zorina ; Cai, Hua. / Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation : Treatment with folic acid. In: Hypertension. 2012 ; Vol. 59, No. 1. pp. 158-166.
@article{528d1c8a4e704b6fbf7d3ad4985d72c3,
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.",
keywords = "abdominal aortic aneurysm, eNOS uncoupling, folic acid, dihydrofolate reductase, hph-1 mice, tetrahydrobiopterin, angiotensin II",
author = "Ling Gao and Siu, {Kin L.} and Karel Chalupsky and Andrew Nguyen and Peng Chen and Weintraub, {Neal Lee} and Zorina Galis and Hua Cai",
year = "2012",
month = "1",
day = "1",
doi = "10.1161/HYPERTENSIONAHA.111.181644",
language = "English (US)",
volume = "59",
pages = "158--166",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation

T2 - Treatment with folic acid

AU - Gao, Ling

AU - Siu, Kin L.

AU - Chalupsky, Karel

AU - Nguyen, Andrew

AU - Chen, Peng

AU - Weintraub, Neal Lee

AU - Galis, Zorina

AU - Cai, Hua

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

AB - 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.

KW - abdominal aortic aneurysm, eNOS uncoupling

KW - folic acid, dihydrofolate reductase

KW - hph-1 mice

KW - tetrahydrobiopterin, angiotensin II

UR - http://www.scopus.com/inward/record.url?scp=83655167072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83655167072&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.111.181644

DO - 10.1161/HYPERTENSIONAHA.111.181644

M3 - Article

C2 - 22083158

AN - SCOPUS:83655167072

VL - 59

SP - 158

EP - 166

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 1

ER -