Our long-range goal is to clarify cellular events during vascular injury by toxic chemicals. Our continued focus on allylamine (AA)-metabolism to a toxic aldehyde, acrolein, that causes probable mitochondrial injury (and a later vascular proliferative response) will be augmented by studies of the mechanism of large vessel necrotizing injury in a new model of vascular toxic synergism (AA plus beta-aminopriopionitrile, or betaAPN). We will dissect early metabolic events occurring in vascular smooth muscle cells, weighing the contribution of acrolein's direct attack on cellular nucleophiles vs. the contribution of H2O2 and reactive oxygen species to toxicity. The potential role and mechanisms of injury to the proposed target organelle, mitochondria, will be examined. We will define altered growth and cell division characteristics of vascular (aortic, endothelial and medial) cells due to acute AA exposure in cells derived from rats treated in vivo with AA. We will characterize early response genes (c-myc, c-fos) heat shock proteins (HSP70) and expression of growth factors. We will define phenotypic changes induced acutely by AA (morphology, cytoskeleton, smooth muscle alpha-actin expression), and ascertain if inhibitors of AA metabolism will obviate these acute responses. To better understand synergistic toxicity, we will do a series of in vitro mechanistic experiments in cultured vascular smoothmuscle cells, their media, and reconstituted enzyme systems to assess the importance of SSAO in vascular damage, and assess the importance of acrolein, glutathione conjugates, adducts, and other toxic metabolites in damage which is proposed to be initiated through targeting of mitochondria. These studies will hopefully lead to an understanding of vascular metabolism, injury, and pathologic responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL026189-15
Application #
2430626
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1980-07-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1999-05-31
Support Year
15
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Salabei, Joshua K; Balakumaran, Arun; Frey, Justin C et al. (2012) Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy. Toxicol Appl Pharmacol 262:265-72
He, N; Singhal, S S; Awasthi, S et al. (1999) Role of glutathione S-transferase 8-8 in allylamine resistance of vascular smooth muscle cells in vitro. Toxicol Appl Pharmacol 158:177-85
Langford, S D; Trent, M B; Balakumaran, A et al. (1999) Developmental vasculotoxicity associated with inhibition of semicarbazide-sensitive amine oxidase. Toxicol Appl Pharmacol 155:237-44
Conklin, D J; Boor, P J (1998) Allylamine cardiovascular toxicity: evidence for aberrant vasoreactivity in rats. Toxicol Appl Pharmacol 148:245-51
Awasthi, S; Boor, P J (1998) Allylamine and beta-aminopropionitrile-induced vascular injury: enhanced expression of high-molecular-weight proteins. J Toxicol Environ Health A 53:61-76
Kumar, D; Trent, M B; Boor, P J (1998) Allylamine and beta-aminopropionitrile induced aortic medial necrosis: mechanisms of synergism. Toxicology 125:107-15
He, N G; Awasthi, S; Singhal, S S et al. (1998) The role of glutathione S-transferases as a defense against reactive electrophiles in the blood vessel wall. Toxicol Appl Pharmacol 152:83-9
Khan, M F; Green, S M; Ansari, G A et al. (1998) Phenylhydroxylamine: role in aniline-associated splenic oxidative stress and induction of subendocardial necrosis. Toxicol Sci 42:64-71
Khan, M F; Boor, P J; Gu, Y et al. (1997) Oxidative stress in the splenotoxicity of aniline. Fundam Appl Toxicol 35:22-30
Langford, S D; Boor, P J (1996) Oleander toxicity: an examination of human and animal toxic exposures. Toxicology 109:1-13

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