The role of microRNA 21 in the development of in-stent restenosis

Coronary heart disease is a major cause of morbidity and mortality worldwide. Percutaneous coronary intervention (PCI) has become the most widely used method of coronary artery revascularisation. The use of stents to hold open atherosclerosis induced arterial narrowing has significantly reduced elastic recoil and acute vessel occlusion following balloon angioplasty. However, bare metal stents have been associated with in-stent restenosis attributed to vascular smooth muscle cell (VSMC) hyperplasia and excessive neointimal formation. The resultant luminal renarrowing may manifest clinically with the return of symptoms such as chest pain or shortness of breath. The development of drug eluting stents has significantly reduced the incidence of in-stent restenosis (ISR). Unfortunately the antiproliferative medications used not only inhibit VSMC proliferation but also re-endothelialisation of the stented vessel. In addition, the drug impregnated polymer coating has been associated with a chronic inflammatory response within the vessel wall predisposing patients to stent thrombosis. Thus the identification of novel therapies which promote vessel healing without excessive proliferative or inflammatory response may improve long term outcome and reduce the need for repeated revascularisation. MicroRNAs (miRs) are short (18-25 nucleotide) non-coding RNAs acting to regulate gene expression. By binding to the 3’untranslated region of mRNA they act to fine tune gene expression either by mRNA degradation or translational repression. Originally identified in coordinating tissue development microRNAs have also been shown to play important roles coordinating the inflammatory response and in numerous cardiovascular diseases. MiR-21 has been identified in human atherosclerotic plaques, arteriosclerosis obliterans and abdominal aortic aneurysms. In addition, its up regulation has been documented in preclinical models of vascular injury. This study sought to identify the role of miR-21 in the development of ISR. Utilising a small animal model of stenting and in vitro techniques, we sought to investigate its influence upon VSMC and immune cell response following stenting. 19 The refinement of a murine stenting model within the Baker laboratory and the electrochemical dissolution of the metal stent from within harvested vascular tissues significantly improved the ability to perform detailed histological analysis. In addition, identification of miRNAs using in situ hybridisation was achieved for the first time within stented tissue. Neointimal formation and ISR was significantly reduced in mice in which miR-21 had been genetically deleted. In addition, neointimal composition was found to be altered in miR-21 KO mice with reductions in VSMC and elastin content demonstrated. Importantly, no difference in re-endothelialisation was observed. In vitro analysis demonstrated that VSMCs from miR-21 KO mice had both reduced proliferative and migratory capacity following platelet derived growth factor stimulation. Molecular analysis revealed that these differences may, at least in part, be due to de-repression of programmed cell death 4 (PDCD4). PDCD4 is a known miR-21 target within VSMCs implicated in the suppression of proliferation and promotion of apoptosis. Unfortunately, initial attempts at antimiR mediated knockdown of miR-21 in vivo, failed to produce a similar change in the suppression of ISR. Furthermore, a significant alteration in macrophage polarisation state within the neointima of miR-21 WT and KO mice was noted. Immunohistochemical staining revealed a preponderance of anti-inflammatory M2 macrophages in KO mice. Analysis of bone marrow derived macrophages from miR-21 KO mice demonstrated an increased level of the peroxisome proliferation activating receptor-γ (PPARγ) which facilitates M2 polarisation. Importantly, significant alterations in numerous pro-inflammatory cytokines, which also have mitogenic effects, were also found following genetic deletion of miR-21. In Summary, this is the first study to look at miRs in the development of ISR. MiR-21 plays an important role in the development of ISR by influencing the proliferative response of VSMCs and modulating the immune response following stent deployment. Further attempts to modulate miR-21 expression following PCI may reduce ISR and the need for repeat revascularisation while also reducing the risk of stent thrombosis.

The development of the accounting professional in a postcolonial context: evidence from Sierra Leone

Despite increasing interest in the development of the accountancy profession and constitutive professional bodies in ex-colonies, little is known about the development of professional accountants as individuals. Similarly, although the continuing influence of the legacies of colonialism and imperialism on the accounting professionalisation trajectory in ex-colonies has been recognised, little attempt has been made to theorise such continuing colonial intervention as a postcolonial condition of accommodation and resistance, with implications for the development of professional accountants. This thesis fills this vacuum by employing four aspects of the critical lens of postcolonial theory – local-global nexus, psycho-existential complex, postcolonial hybridity and diaspora - to gain an insight into the development of accounting professionals in ex-colonies with specific reference to Sierra Leone. Specifically, it examines the current model of accounting professionalisation adopted in Sierra Leone and implications for the development of professional accountants in the country; investigates the historical and ideological legacies of colonialism that shaped and continue to influence the professionalisation trajectory in Sierra Leone; explores the perceptions of Sierra Leonean chartered and aspiring accountants of their professional identity in terms of their professional development within Sierra Leone; and explores the lived experiences of Sierra Leonean chartered and aspiring accountants in the diaspora and the diaspora effect on accountancy in Sierra Leone. The empirical evidence presented here emanated from two sources: a web-based survey and semi-structured interviews with Sierra Leonean chartered and aspiring accountants both within and outside the country at the time of the study. The model for developing professional accountants in Sierra Leone comprises a partnership between the local professional body, ICASL, and the British-based global body, the ACCA. A postcolonial analysis of the empirical evidence reveals that an unintended consequence of this model is that the local is co-opted within the global while the global becomes increasingly localised. The analysis also shows that the presence of a perceived global body ‘inferiorises’ the local body to the point of undesirability among local chartered and aspiring accountants. Thus the partnership has to date done little by way of developing ICASL’s capacity to ensure the development of a localised profession and professionals. Instead, it produces, within the Sierra Leone accountancy space, professional hybrids that at once pose as global as well as local accountants. This has significant implications for the local profession because many of the hybrid professional accountants who could potentially drive the local profession forward end up in the diaspora, which leaves the local profession in a weaker state. Also, given the established link between a robust accountancy profession and sustainable economic development, such professional diasporisation could negatively impact on the country’s economic development. In sum, Sierra Leone has failed to establish an accounting professionalisation model that develops professional accountants (through contextualised professional education and training) that meets the specific accounting needs of its growing economy.