ABCA3, a 150 kDa protein belonging to the ATP-Binding Cassette (ABC) transporter superfamily, has been shown to play a role in surfactant production in humans. However, in bacteria, ABC transporters are known to mediate the flux of nitrite. Biotransformation of glyceryl trinitrate (GTN), a drug used in the treatment of heart conditions such as angina pectoris and heart failure, yields the inorganic nitrite anion, and the intracellular oxidation of this ion may lead to the formation of tyrosine-nitrated proteins and cellular damage. Immunohistochemical studies indicate the presence of ABCA3 in rat aortic smooth muscle and endothelial cells. My objective was to assess whether changes in either ABCA3 mRNA expression or nitrite accumulation occur during chronic exposure to GTN. Accordingly, male Sprague-Dawley rats were exposed to 0.4 mg/hr GTN for 48 hours to induce GTN tolerance, and the aortas removed. Nitrite and ABCA3 mRNA levels were assessed using the Greiss colorimetric assay, and real-time or semi-quantitative RT-PCR, respectively. In control aortas, endothelium removal resulted in an apparent 25-35% decrease in ABCA3 mRNA levels, indicating that the transporter is expressed in endothelial cells more abundantly than in smooth muscle cells since the ratio of endothelial cells to smooth muscle cells in the rat aorta is approximately 10:1. Furthermore, ABCA3 mRNA levels were decreased by 70% in aortas from GTN-tolerant animals, whereas the mRNA levels of a related transporter, ABCA1, remained at control levels. An inverse correlation between nitrite and ABCA3 mRNA levels occurred after the induction of GTN tolerance, with an apparent redistribution of nitrite to endothelial cells. These findings indicate that chronic GTN exposure results in altered expression of ABCA3, and that this is associated with altered nitrite distribution in blood vessels from GTN-tolerant animals. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2009-06-23 14:18:16.122
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/1968 |
| Date | 24 June 2009 |
| Creators | Hampton, ASHLEIGH |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | 1224888 bytes, application/pdf |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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