Involvement of semicarbazide-sensitive amine oxidase-mediated deamination in atherogenesis in KKAy diabetic mice fed with high cholesterol diet.
OBJECTIVE
Semicarbazide-sensitive amine oxidase has been recognised to be a potential risk factor in vascular disorders associated with diabetic complications and to be related to mortality in patients suffering from heart disease. This enzyme, associated with the vascular system, catalyses the deamination of methylamine and aminoacetone, and also acts as an adhesion molecule related to leucocyte trafficking and inflammation. The deaminated products include the toxic aldehydes, formaldehyde and methylglyoxal, respectively, hydrogen peroxide and ammonia.


METHODS
In this study, the KKAy mouse, a strain possessing features closely resembling those of Type II (non-insulin-dependent) diabetes mellitus has been used to substantiate the hypothesis. Vascular lesions were induced via chronic feeding of a high cholesterol diet.


RESULTS
Both MDL-72974A, a selective mechanism-based semicarbazide-sensitive amine oxidase inhibitor and aminoguanidine effectively inhibited aorta semicarbazide-sensitive amine oxidase activity, and caused a substantial increase in urinary methylamine, and a decrease in formaldehyde and methylgloxal levels. Inhibition of semicarbazide-sensitive amine oxidase also reduced oxidative stress, as shown by a reduction of malondialdehyde excretion. Both MDL-72974A and aminoguanidine reduced albuminuria, proteinuria and the number of atherosclerotic lesions in animals fed with a cholesterol diet over a period of treatment for 16 weeks.


CONCLUSIONS
Increased semicarbazide-sensitive amine oxidase-mediated deamination could be involved in the cascade of atherogenesis related to diabetic complications.
Yu
P H
PH
Neuropsychiatry Research Unit, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. yup@usask.ca
Wang
M
M
Deng
Y L
YL
Fan
H
H
Shira-Bock
L
L
D000419:Albuminuria / Q000453:epidemiology / Q000503:physiopathology*; D000498:Allyl Compounds / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000588:Amines / Q000378:metabolism; D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology* / Q000652:urine; D002082:Butylamines / Q000494:pharmacology; D002791:Cholesterol, Dietary; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology* / Q000652:urine; D003925:Diabetic Angiopathies / Q000503:physiopathology* / Q000652:urine; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D008744:Methylamines / Q000652:urine; D051379:Mice; D008815:Mice, Inbred Strains
D000498:Allyl Compounds; D000588:Amines; D002082:Butylamines; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D006146:Guanidines; D008744:Methylamines; C058000:mofegiline; C027451:methylamine; D006631:Amine Oxidase (Copper-Containing); C004479:pimagedine