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Oxidative stress compromises vasomotor function of the thoracic aorta in Marfan Syndrome Yang, Huei-Hsin Clarice

Abstract

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.

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