TY - JOUR
T1 - Developmental vasculotoxicity associated with inhibition of semicarbazide-sensitive amine oxidase
AU - Langford, S. D.
AU - Trent, M. B.
AU - Balakumaran, A.
AU - Boor, P. J.
N1 - Funding Information:
The authors express their gratitude to Mr. J. Wait, Dr. R. Bukowski, Dr. R. Fritz (UTMB Protein Chemistry Core Laboratory), and Mrs. Judith Bailes for their respective contributions to the completion of this study. We thank Drs. D. M. Palfreyman and E. H. W. Böhme of Marion Merrell Dow Research Institute for kindly supplying MDL-72274 and MDL-72145. This work was supported by grants to S. D. L. (National Institute of Environmental Health Sciences Toxicology Training Grant T32ES07254, United States Environmental Protection Agency Fellowship U-915014-01-2, and the UTMB Sealy Center on Aging Grant O-18311-644400-10) and to P. J. Boor (National Institutes of Health Grant HL-26189). Although the research described in this article has been funded in part by the United States Environmental Protection Agency under the assistance agreement listed above, it has not been subjected to the EPA’s peer and administrative review and, therefore, may not necessarily reflect the views of the agency, and no official endorsement should be inferred.
PY - 1999/3/15
Y1 - 1999/3/15
N2 - The endogenous substrate(s) and physiological function(s) of semicarbazide-sensitive amine oxidase (SSAO), a group of enzymes exhibiting highest activity in vascular smooth muscle cells of the mammalian aortic wall, remain undetermined. This study examines the pathophysiological effects in the thoracic aortic wall resulting from specific in vivo SSAO inhibition. Weanling Sprague-Dawley rats were treated acutely or chronically with either semicarbazide hydrochloride or the allylamine derivatives MDL-72274 or MDL- 72145 (Marion Merrell Dow Research Institute, Cincinnati, OH). Treatment with these compounds produced acute (6 and 24 h) and chronic (21 day) lowering of SSAO activity in aorta and lung with little effect on the activity of the vital matrix-forming enzyme, lysyl oxidase, in aortas of chronically treated animals. Chronic SSAO inhibition produced lesions consisting of striking disorganization of elastin architecture within the aortic media accompanied by degenerative medial changes and metaplastic changes in vascular smooth muscle cells. No significant difference in the total weight of dry, lipid- extracted aortic elastin and collagen components were observed between chronically SSAO inhibited and control animals. However, the amount of mature elastin was lowered and mature collagen was raised in the aortas of animals treated chronically with semicarbazide. Descending thoracic aortic rings isolated from chronically SSAO-inhibited animals had larger cross-sectional diameters (i.e., exhibited dilation) when compared to corresponding rings from control animals. This study demonstrates that developmental toxicity, characterized by striking vascular lesions and dilated thoracic aortas, can result from specific in vivo SSAO inhibition, suggesting a role for SSAO in connective tissue matrix development and maintenance, and specifically in the development of normal elastin.
AB - The endogenous substrate(s) and physiological function(s) of semicarbazide-sensitive amine oxidase (SSAO), a group of enzymes exhibiting highest activity in vascular smooth muscle cells of the mammalian aortic wall, remain undetermined. This study examines the pathophysiological effects in the thoracic aortic wall resulting from specific in vivo SSAO inhibition. Weanling Sprague-Dawley rats were treated acutely or chronically with either semicarbazide hydrochloride or the allylamine derivatives MDL-72274 or MDL- 72145 (Marion Merrell Dow Research Institute, Cincinnati, OH). Treatment with these compounds produced acute (6 and 24 h) and chronic (21 day) lowering of SSAO activity in aorta and lung with little effect on the activity of the vital matrix-forming enzyme, lysyl oxidase, in aortas of chronically treated animals. Chronic SSAO inhibition produced lesions consisting of striking disorganization of elastin architecture within the aortic media accompanied by degenerative medial changes and metaplastic changes in vascular smooth muscle cells. No significant difference in the total weight of dry, lipid- extracted aortic elastin and collagen components were observed between chronically SSAO inhibited and control animals. However, the amount of mature elastin was lowered and mature collagen was raised in the aortas of animals treated chronically with semicarbazide. Descending thoracic aortic rings isolated from chronically SSAO-inhibited animals had larger cross-sectional diameters (i.e., exhibited dilation) when compared to corresponding rings from control animals. This study demonstrates that developmental toxicity, characterized by striking vascular lesions and dilated thoracic aortas, can result from specific in vivo SSAO inhibition, suggesting a role for SSAO in connective tissue matrix development and maintenance, and specifically in the development of normal elastin.
KW - Aorta
KW - Collagen
KW - Developmental toxicity
KW - Elastin
KW - Lysyl oxidase
KW - Semicarbazide-sensitive amine oxidase
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U2 - 10.1006/taap.1998.8602
DO - 10.1006/taap.1998.8602
M3 - Article
C2 - 10079209
AN - SCOPUS:0033559848
SN - 0041-008X
VL - 155
SP - 237
EP - 244
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 3
ER -