期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 150, 期 8, 页码 1075-1083出版社
WILEY
DOI: 10.1038/sj.bjp.0707181
关键词
Marfan syndrome; endothelium-dependent relaxation; nitric oxide; thoracic aorta; acetylcholine; Akt; age-related disease progression
资金
- NIAMS NIH HHS [R01 AR041135, AR41135, AR049698, P01 AR049698] Funding Source: Medline
Background and purpose: Aortic complications account for the major mortality in Marfan syndrome ( MFS), a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1. We hypothesized that MFS impaired endothelial function and nitric oxide ( NO) production in the aorta. Experimental approach: Mice ( at 3, 6, 9 and 12 months of age) heterozygous for the Fbn1 allele encoding a cysteine substitution ( Fbn1(C1039G/+), Marfan mice, n = 75), the most common class of mutation in MFS, were compared with age-matched control littermates ( n = 75). Thoracic and abdominal aortas from the two groups were studied. Key results: Isometric force measurements revealed that relaxation to ACh ( but not to sodium nitroprusside) was diminished in the phenylephrine-precontracted Marfan thoracic aorta at 6 months of age ( pEC(50) = 6.127 +/- 0.22; maximal response, E-max 52.7 +/- 6.8%; control: pEC(50) = 7.34 +/- 0.19; E-max 84.8 +/- 2.2%). At one year, both inhibition of NO production with N-omega-nitro-L- arginine methyl ester, or denudation of endothelium increased the phenylephrine-stimulated contraction in the control thoracic aorta by 35%, but had no effect in the Marfan aorta, indicating a loss of basal NO production in the Marfan vessel. From 6 months, a reduced phosphorylation of endothelial NOS ( eNOS) (Ser1177) and Akt(Thr308) detected by Western blotting was observed in the Marfan thoracic aorta, which was accompanied by decreased levels of cGMP. Expressions of Akt and eNOS in the abdominal aorta were not different between the two groups. Conclusions and Implications: MFS impairs endothelial function and signaling of NO production in the thoracic aorta, suggesting the importance of NO in the age-related progression of thoracic aortic manifestations.
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