I024 Comparison of the effects of semicarbazide and beta-aminopropionitrile on arteries in the brown norway rat

Abstract

Semicarbazide-sensitive amine oxidase (SSAO) is highly expressed by the smooth muscle cells of the aorta but its function within the arterial wall is unknown. This contrasts with another lifeessential amine oxidase expressed in the aortic wall, lysyl oxidase (LO), responsible for post-translational cross-linking of tropoelastin and collagen molecules to produce insoluble, highly mechanically resistant fibres. It has been hypothesized that SSAO may participate in extracellular matrix cross-linking, but proof is lacking. To investigate whether SSAO may play such a role physiologically, we compared effects of semicarbazide (SCZ) and β-aminopropionitrile (BAPN), two amine oxidase inhibitors with different properties and relative specificities for SSAO and LO, on arteries in growing Brown Norway rats, which present a rare phenotype of spontaneous rupture of the internal elastic lamina (IEL) that is aggravated by LO inhibition. We measured aortic LO and SSAO activities during and at the end of 8-9 weeks of treatment, started at weaning, and quantified aortic insoluble elastin and total collagen contents, IEL ruptures in several arteries, ex vivo carotid artery wall rupture pressure and solubility of tail tendon collagen. After a pilot study using equivalent doses by weight, and combining the two compounds to test for additivity, we performed a study using low and high equimolar doses of SCZ and BAPN. Both compounds similarly inhibited LO, whereas SCZ was far more effective than BAPN in inhibiting SSAO. Both compounds decreased carotid rupture pressure, increased collagen solubility, decreased aortic insoluble elastin (% dry weight) and also increased IEL ruptures in abdominal aorta, iliac, renal and caudal arteries in a dose-dependent manner. The high dose of SCZ increased aortic collagen and extracellular proteins other than insoluble elastin markedly more than did equimolar BAPN, possibly revealing a specific effect of SSAO inhibition. We conclude that the majority of SCZ effects are mediated by LO inhibition, SCZ being more effective than BAPN in our in vivo experimental conditions, and to demonstrate unequivocally a specific effect of SSAO inhibition on extracellular matrix formation or organization, we must await availability of more specific inhibitors.