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Oxidative stress compromises vasomotor function of the thoracic aorta in Marfan Syndrome

University of British Columbia

Introduction: Marfan syndrome is an autosomal dominant connective tissue disorder that causes life-threatening cardiovascular complications such as thoracic aortic dilatation and aneurysm. We have demonstrated that Marfan syndrome compromises contractile function of the aorta and impairs nitric oxide-mediated relaxation. We hypothesize that oxidative stress impairs contractility and endothelium-dependent relaxation in the thoracic aorta of Marfan mice. Methods: Adrenergic contractions and cholinergic relaxations of thoracic aorta from mice heterozygous for FBN1 allele (Fbn1C¹⁰³⁹G/+ , n=40; age=3,6,9 months), a well-defined model of Marfan syndrome, were compared with those from control littermates (n=40). Results: At 3 and 6 months, oxidative stress, as indicated by the plasma 8-isoprostane level, was 50% greater in the Marfan group than in the control. In 9 months old Marfan mice, the depressed phenylephrine-induced contraction was normalized by the preincubation of superoxide dismutase (SOD) which increased the maximal contractile response (Emax) and pEC₅₀ for phenylephrine-stimulated contraction by 91% and 2.75-fold. The compromised endothelial function was also restored by SOD which increased the sensitivity to acetylcholine by 10.7 and 12.3-fold at 3 and 6 months, respectively. Such improvement was absent in the controls. In 9 months old Marfan mice, the phenylephrine-contraction was potentiated 141% by 1400W, an inducible nitric oxide synthase (iNOS) inhibitor. The pEC₅₀ was normalized by 1400W and allopurinol, an inhibitor of xanthine oxidase. In the same group, both Emax and pEC₅₀ of acetyicholine was normalized by apocynin, an inhibitor of NAD(P)H oxidase. Protein expression of SOD was decreased at 3 and 9 months in the Marfan group, whereas expression of xanthine oxidase, iNOS, gp9lphox, p47phox and p67phox, the subunits of NAD(P)H oxidase, was all increased. Conclusions: The compromised vasomotor function in Marfan thoracic aorta could be associated with oxidative stress resulting from decreased expression of SOD and increased expression of iNOS, xanthine oxidase, and NAD(P)H oxidase.

Thesis/Dissertation

application/pdf

2009-11-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/15003

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/