Atherosclerosis is a chronic inflammatory condition of larger arteries characterized by build-up of plaques in the vessel wall. Disruption of plaques results in superimposed thrombus formation, or atherothrombosis, leading to the occlusion of the blood vessels. Atherosclerosis is the primary cause of heart attacks and strokes. Recent studies show that various fibrinolytic factors influence atherosclerosis progression. A healthy fibrinolytic system is fundamental to mitigating the worsening of the lesion and atherosclerosis progression by rapidly removing unwanted microthrombi that is otherwise incorporated into the plaque. In this regard, the activated thrombin-activable fibrinolysis inhibitor (TAFIa), a potent antifibrinolytic metallocarboxypeptidase that attenuates clot dissolution, could influence atherosclerosis progression. Aside from its antifibrinolytic property, TAFIa also affects inflammation by inactivating anaphylatoxins and kinins. Therefore, TAFIa possesses the potential to influence atherosclerosis via antifibrinolytic and anti-inflammatory facets. We utilized mice deficient in apolipoprotein E (ApoE-/-) as a model of atherosclerosis. Characterization of murine TAFIa determined that the functional half-lives at 37 and 25 ˚C were about 4.0 and 12.7 minutes, respectively. TAFIa was stable indefinitely at 0 ˚C. In vitro clot lysis assays were performed on the plasmas of C57BL/6J (wild-type) and ApoE-/- mice, aged 5, 10, 15 and 30+ weeks. No differences in clot lysis times were observed between the two genotypic classifications. TAFIa was directly quantified using our in-house assay, which showed decreased TAFIa levels in the ApoE-/- mice. Closer examination revealed that the plasma from the ApoE-/- mice was negatively influencing the TAFIa assay. Total TAFI zymogen levels in these samples appeared to increase with age. Other biomarkers of inflammation were quantified using ELISAs; however, only IL-10 levels were measurable with slight elevation in the ApoE-/- mice across age, while IL-1beta, TNF-alpha, and IL-6 was unquantifiable. Overall, TAFIa does not appear to influence atherosclerosis progression in ApoE-/- mice. / Thesis / Master of Science (MSc) / Atherosclerosis is an inflammatory disease of large blood vessels that leads to unwanted clot formation on these weakened/compromised vessel walls. Eventually, the blood flow is hindered by these clots and the supply of oxygen and nutrients to vital organs are disrupted, leading to irreparable damage and death of these organs. As such, it, is the primary cause of heart attacks and strokes depending on the location of vessel occlusion. Thrombin activable fibrinolysis inhibitor (TAFI), when activated to TAFIa, contains both anti-inflammatory and antifibrinolytic properties. Therefore, it is likely that TAFI(a) would be involved in atherosclerosis development and/or progression, especially since other fibrinolytic factors have shown to be involved. Despite promising preliminary data, we found that TAFI(a) alone may minimally be involved in the overall atherosclerosis progression and development using a mouse model of atherosclerosis. We further investigate whether TAFI(a) can be used as a biomarker for early diagnosis of atherosclerosis.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24101 |
| Date | January 2018 |
| Creators | Muzafar Gani, Dhulfiha |
| Contributors | Kim, Paul, Medical Sciences (Thrombosis & Haemostasis & Atherosclerosis) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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