Modifications of Arterial Phenotype in Response to Amine Oxidase Inhibition by Semicarbazide

Abstract

Semicarbazide-sensitive amine oxidase (SSAO)-deficient mice present no alteration in elastin cross-linking processes and carotid mechanical properties. In contrast, previous studies have shown that SSAO inhibitors induced marked anomalies in arterial structure and function. The aim of the present study was to examine the effect of semicarbazide (SCZ), an efficient SSAO inhibitor, on the arterial phenotype of the carotid artery in relation to modulation of SSAO and lysyl oxidase activities in growing rats. We first show that after 6 weeks of SCZ treatment (100 mg/kg per day), SSAO activity was reduced by 90%, whereas lysyl oxidase activity was only partially inhibited (<60%) in carotid artery, compared with controls. There was significant growth inhibition and no difference in mean arterial pressure but an increase in pulse pressure with a smaller arterial diameter in SCZ-treated rats. SCZ decreased aortic insoluble elastin without a change in total collagen. In addition, extracellular proteins other than insoluble elastin and collagen were increased in SCZ-treated rats. All of the elastic lamellae presented globular masses along their periphery, and focal disorganization was observed in the ascending aorta. Carotid artery mechanical strength was lower in SCZ-treated rats, and the elastic modulus-wall stress curve was shifted leftward compared with controls, indicating increased stiffness. Thus, SCZ modifies arterial geometry and mechanical properties, alters elastic fiber structure, and reduces the content of cross-linked elastin. Because these abnormalities are essentially absent in SSAO-deficient mice, our results suggest that lysyl oxidase inhibition is responsible for the major part of the vascular phenotype of SCZ-treated rats.