Atherosclerosis, a vascular disease which may lead to coronary artery occlusion and consequent myocardial infarction is primarily caused by dyslipidemia. Ischemic cardiomyopathy due to atherosclerosis is the leading cause of morbidity and mortality in the western world today. Vasoactive factors are increasingly being recognized not only as contributors to atherosclerotic plaque formation, but also to cardiac function and remodeling following ischemic cardiac injury. Urotensin II (UII) is one such vasoactive factor. UII possesses a wide range of cardiovascular effects, from contraction of the rat aorta to complete cardiovascular collapse in cynomolgus monkeys. UII binds a seven transmembrane spanning G-protein coupled receptor termed UT. Expression of UII is significantly elevated in the hearts of patients with congestive heart failure (CHF). Recent reports have also shown increased plasma levels of the peptide in patients with CHF, and these levels correlated with the severity of the disease. This project was designed to investigate the role of UII and UT in both atherosclerosis and CHF. To this end, UII expression was evaluated both in a model of CHF in the rat, and in human atherosclerosis of the carotid arteries and aortae. Furthermore, the pathophysiological role of urotensin-I1 in CHF was investigated, with the use of a selective UII antagonist, SB-611812. Finally, genetically modified mice deficient in either ApoE, UT, or both genes, were evaluated to study the role of UII/UT signaling in a model of atherosclerosis. We found that UII and its receptor, UT, were both significantly elevated in a model of CHF induced by coronary artery ligation. UII antagonism significantly attenuated mortality, cardiac dysfunction, and hypertrophy. This was associated with a significant decrease in cardiac fibrosis. We next went on to demonstrate that UII and UT were significantly elevated in human atherosclerotic carotid arteries and aortae. Finally, we demonstrated that deletion of the UT gene in mice deficient for ApoE exacerbates atherosclerosis of the aorta. Furthermore, this was associated with significantly increased hyperlipidemia and organ hypertrophy as well as significantly reduced body mass, liver mass, and hepatic steatosis. / In conclusion we were the first to demonstrate a pathophysiological role for UII in cardiovascular diseases which may lead to a breakthrough in the management of CHF and may also give more insight into the pathogenesis of atherosclerosis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111848 |
| Date | January 2007 |
| Creators | Bousette, Nicolas. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002584336, proquestno: AAINR32295, Theses scanned by UMI/ProQuest. |
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