Cell contact dependent events involving CD151 in atherosclerosis and atherothrombosis

Saiful Rijal, K 2014, Cell contact dependent events involving CD151 in atherosclerosis and atherothrombosis, Doctor of Philosophy (PhD), Medical Sciences, RMIT University.


Document type: Thesis
Collection: Theses

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Title Cell contact dependent events involving CD151 in atherosclerosis and atherothrombosis
Author(s) Saiful Rijal, K
Year 2014
Abstract Ischaemic heart disease is the leading cause of death worldwide. Platelets are central in normal haemostasis to arrest bleeding following trauma and under pathological conditions of atherosclerotic plaque rupture and arterial thrombosis. The development of platelet thrombi leads to the clinical sequela of cardiovascular disease which in 2011 accounted for 31% of all deaths in Australia.(1) Ischaemic heart disease accounted for 14.65% of all deaths nationwide in 2011.(2)

Numerous factors are implicated in increasing the thrombogenic potential of ruptured plaques including increased blood shear rates in narrowed blood vessels and responsiveness of platelet activation. CD151 is a tetraspanin amongst several found on platelets. It is a promising target in anti-platelet therapies, acting in conjunction with cognate receptors particularly integrin αIIbb3 in the regulation of platelet thrombus formation in vivo. The functional and physical associations between CD151 and integrin αIIbb3 in murine platelets emphasises the critical involvement of CD151 in modulating outside-in αIIbb3 signalling pathways.(3)

A novel ApoE-/-.CD151-/- model was developed by crossing the ApoE-/- genotype with the CD151-/- genotype. CD151 has not been studied in the context of atherosclerosis and through this model, in vivo and in vitro studies were able to be performed. The ApoE-/-.CD151-/- model was characterised for its Mendelian inheritance profile, haematological and lipid parameters and cardiovascular risk factors such as body weight, age, body mass index and glucose levels. The Mendelian inheritance frequencies for the ApoE-/-.CD151-/- ­was significantly altered whilst lipid profiles showed reduced total cholesterol and high density lipoprotein cholesterol levels in comparison to ApoE-/- mice. The remaining parameters appeared normal.

Preliminary histology and immunohistochemistry studies indicated a significantly reduced plaque burden in the ApoE-/-.CD151-/- mouse compared to the ApoE-/- mouse through haematoxylin and eosin staining of the aortic valve cusps. Plaque composition was unchanged in the absence of CD151 in atherosclerosis. This was determined through immunohistochemical staining for F4/80 pan macrophage markers, smooth muscle actin, type 1 collagen and CD151 expression.

In vivo studies demonstrated a defect in ApoE-/-.CD151-/- platelets with prolonged times to occlusion upon FeCl3 induced vascular injury of the carotid arteries and reduced thrombus formation in comparison to ApoE-/- platelets. In vivo tail bleeding assays similarly suggested a defect of unstable haemostasis as bleeding times, volume of blood lost and rebleeds were significantly increased in the ApoE-/-.CD151-/- model. Platelet aggregation responses appeared unchanged between the strains implying that CD151 absence had no protective effect on agonist induced platelet aggregation. Furthermore, we saw a similar pattern in our in vivo studies of the mesenteric arterioles whereby, thrombus area, volume and stability mirrored that of CD151+/+ findings from previous studies.

We have contributed further to the understanding of tetraspanin CD151 in platelet thrombus formation models in vivo and its influence on plaque burden in atherosclerosis. The potential of CD151 as an anti-thrombotic target for the development of novel anti thrombotics for cardiovascular diseases and cerebrovascular ischaemic diseases has been identified. The findings will need to be elucidated further by the inclusion of in vivo studies on other vascular beds in a mouse model.

References

1. National Heart Foundation of Australia. Data and statistics Australia: Heart Foundation [Internet]. 2011 [updated 2014; cited 2014 July 25]. Available from: http://www.heartfoundation.org.au/information-for-professionals/data-and-statistics/Pages/default.aspx

2. Australian Bureau of Statistics. 3303.0 - Causes of death, Australia, 2011: Australian bureau of statistics. 2013 [updated 2014 March 24; cited 2014 July 23].

3. Lau LM, Wee JL, Wright MD, Moseley G, Hogarth PM, Ashman LK, et al. The tetraspanin superfamily member CD 151 regulates outside-in integrin αIIbβ3 signaling and platelet function. Blood. 2004;104:2368 - 2375.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Medical Sciences
Keyword(s) atherothrombosis
atherosclerosis
cd151
platelet cd151
thrombus formation
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