Investigation of microRNA-516a-5p, microRNA-1260 and low-density lipoprotein receptor-related protein-1 in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a vascular disease which the abdominal aorta is enlarged by 50% or more of its normal diameter, potentially posing a threat to life as it may rupture and result in massive internal haemorrhage. Although AAA can be treated by surgical repair, there is still no effective method to prevent AAA formation as the ultimate causes of AAA still remain unknown. Existing literature has suggested that extracellular matrix (ECM) turnover and inflammation are well-established key processes in AAA progression, and it is believed that these key processes may be tightly regulated by certain components for determination of AAA formation. Therefore, this thesis aims to find out the causes of AAA through the investigation of regulatory roles of some potential participants in AAA pathogenesis. The first study focused on two specific microRNAs (miRNAs), i.e. miR-516a-5p and miR-1260, which were found up- and down-regulated respectively in vascular smooth muscle cells (VSMCs) cultured from AAA patients in a miRNA microarray profiling assay, hypothesizing that these two differentially expressed miRNAs may involve in AAA pathogenesis. The aim of this study is to investigate whether miR-516a-5p and miR-1260 involve in regulating AAA key pathogenic processes. Current findings found that miR-516a-5p may regulate matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1 and methylenetetrahydrofolate reductase expressions in human VSMCs, suggesting that miR-516a-5p overexpression in VSMCs may promote AAA formation through proteolytic degradation of elastin in ECM of aortic wall and inhibition of homocysteine metabolism. On the other hand, miR-1260 may regulate collagen type 1 alpha 1 and monocyte chemoattractant protein-1 expressions in human VSMC, suggesting that miR-1260 suppression in VSMCs may promote AAA progression through activation of collagen remodeling and inflammatory response. The second study focused on low-density lipoprotein receptor-related protein-1 (LRP1) which is proposed to be a regulator of AAA pathogenesis by some genome association and animal studies but without validation in human study. The aim of this study is to first investigate the LRP1 protein expression in AAA compared against control tissues from humans, followed by investigation of upstream and downstream regulations of LRP1 for AAA pathogenesis. Current results suggested that a reduced LRP1 protein expression was associated with AAA progression in human samples. The differential LRP1 protein expression in human AAA tissues may be tightly regulated by miR-205 through translational inhibition in human VSMCs. Moreover, it is observed that the LRP1 protein expression on human VSMCs may mediate the clearance of pericellular matrix metalloproteinase-9 (MMP-9). These suggested that a reduced LRP1 protein expression in VSMCs, which may be tightly regulated by miR-205, may result in a reduced MMP-9 clearance from ECM and hence an increased proteolytic degradation of elastin in ECM of abdominal aortic wall for AAA progression. In conclusion, the studies provide an insight that miR-516a-5p, miR-1260 and LRP1 in human VSMCs from abdominal aortic tissues may have different roles in regulating AAA pathogenic processes.published_or_final_versionSurgeryDoctoralDoctor of Philosoph