Ras genes as molecular targets of benzo(a)pyrene in vascular smooth muscle cells : implications in atherogenesis /
The present studies were conducted to define molecular
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1996.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=739669331&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The present studies were conducted to define molecular targets of benzo(a)pyrene (BaP) in vascular smooth muscle cells (SMCs), a key cellular component of atherosclerotic plaques. Male Sprague Dawley rats were injected intraperitoneally with 10 mg/kg BaP or an equivalent volume of vehicle for 5, 8, or 12 weeks. Histological evaluation of thoracic aortae showed increased atherosclerotic lesion development as a function of time in BaP-treated animals. Early lesions were characterized by increased volume between laminae and expansion of extracellular matrix at 5 weeks. Local foci protruding into the vessel lumen characterized by fragmentation of the elastic laminae, increased SMC mass, and a dramatic change in SMC orientation were found at 8 weeks . By 12 weeks, neoplastic outgrowth was observed in the aortic wall of I of 3 BaP-treated rats, but not in any of the control animals. Immunohistological staining with a monoclonal Ras antibody showed localized immunoreactivity in the aorta of BaP-treated rats. Aortic SMCs isolated from BaP-treated animals exhibited a proliferative phenotype characterized by elevated PI 3-kinase activity and up- regulated c-Ha-ras gene expression. No mutations in codons 12, 13, and 61 of cHa-, c-Ki-, and N-ras genes were observed in BaP SMCs, indicating that uncontrolled proliferation was not mediated by mutations in these regions. Measurements of mRNA stability showed that BaP treatment accelerated c-Ha-ras mRNA degradation. No mutagenic effects of BaP were found in critical alternative splicing sites. BaP did not affect transcriptional start site selection of c-Ha-ras, but enhanced overall transcription rates. Alternative genes influenced by BaP in vascular SMCs, including retrotransponsons, were tentatively identified by differential display PCR. Based on these observations we conclude that BaP exerts an atherogenic effect in rats in vivo characterized by up-regulation of ras gene function. In vitro, the ability of BaP to influence ras appears to be restricted to a transcriptional mechanism that results in overall enhancement of ras RNA levels. The extent to which enhancement of ras expression interacts with other genetic abnormalities following BaP treatment remains to be defined. |
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| Item Description: | Vita. "Major Subject: Toxicology". |
| Physical Description: | 1x, 120 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references: pages 94-119. |