The significance of glucose transporters in the pathogenesis of abdominal aortic aneurysms

Abdominal aortic aneurysm (AAA) is associated with significant mortality worldwide. At present, the only treatment involves an operation. Understanding the pathogenesis is important to help develop new drug therapies aimed at slowing aneurysm growth. Diabetes mellitus (DM) has been shown to be negatively associated with AAA however the mechanisms underlying this relationship are poorly understood. This thesis first confirmed the robustness of this epidemiological relationship through a meta-analysis of >70 studies and then, using whole aortic tissue samples (WATS) and aortic smooth muscle cells (AoSMCs) from patients with and without AAA, examined the importance of glucose transporters (GLUTs), a group of proteins responsible for sugar transport across cell membranes, in the pathogenesis of AAA and in explaining the negative relationship between DM and AAA. Comparing WATS from patients with and without AAA, gene expression of GLUT3 (p=0.004) and GLUT6 (p=0.04) and protein expression of GLUT1 (p=0.002), GLUT3 (p=0.002) and GLUT6 (p=0.004) were significantly higher in WATS from AAA patients. Comparing AoSMCs from patients with and without AAA, gene expression of GLUTs was similar between groups however GLUT activity was significantly higher in AoSMCs from patients with AAA (p=0.02). To study the effect of DM on GLUTs, AoSMCs from patients with and without AAA were exposed to increasing levels of hyperglycaemia (4.6mmol/L - 50mmol/L). Hyperglycaemia was not associated with a significant change in the gene expression of GLUTs, cathepsins or TIMPs, however hyperglycaemia within the physiological range (up to 25mmol/L) was associated with a significant decrease in GLUT activity (p=0.01) selectively in the AoSMCs from AAA patients, independent of any hyperosmolar effect. In conclusion, these results suggest that glucose transporters are important in the pathogenesis of AAA and may be involved in regulating the protective effect of DM on AAA. Targeting glucose transporters to slow aneurysm growth merits further investigation.