Amanda Balboa Ramilo: Exploring Preclinical Targets in Abdominal Aortic Aneurysm

Abstract

Abdominal Aortic Aneurysm (AAA) is a vascular disease characterised by the progressive and permanent dilation of the aorta, culminating in rupture and death, if not intervened. It affects 5% of men over the age of 65 years with a history of smoking. No pharmacological options are available to treat this disease. This thesis aims to investigate the role of glucose metabolism and mitochondrial function (Studies I-III) and microRNAs (Study IV) in experimental AAA and evaluate their potential as treatment targets.

In Study I, angiotensin II (angII)-infused Apolipoprotein E (ApoE) deficient mice received intraperitoneal injections of the glycolysis inhibitor PFK15, for three weeks, starting one week after disease induction. Treatment with PFK15 reduced aneurysm formation compared with the control group and prevented the decrease in α-smooth cell actin/vimentin gene expression ratio caused by angII. Glycolysis inhibition with PFK15 prevents AAA growth by favouring the maintenance of a contractile phenotype of vascular smooth muscle cells.

In Study II, angII-infused ApoE deficient mice received daily subcutaneous injections of the glucagon-like peptide 1 receptor analogue semaglutide, for four weeks, starting simultaneously with disease induction. Treatment with semaglutide prevented death by aortic rupture in the first seven days of disease development and the loss of collagen in the aortic wall. Semaglutide thereby prevents aortic dissection and rupture likely by promoting the maintenance of collagen in the aortic wall. 

In Study III, mice received angII or saline infusion for four weeks. Mitochondrial function was evaluated ex vivo in whole aortic tissue, by high-resolution respirometry. Aortas of angII-infused mice had a reduced capacity to increase oxygen consumption, in response to ADP and succinate, compared to control. These results demonstrate that it is possible to measure mitochondrial function in whole aneurysmal tissue ex vivo, and, importantly, that mitochondrial function is impaired in AAA. 

In Study IV, angII-infused ApoE deficient mice received four intraperitoneal injections of miR-10b, starting three days before disease induction and continuing for four weeks. Treatment with miR-10b promoted AAA development, growth and rupture, associated with an increased elastin degradation. miR-10b has an active role in promoting experimental AAA progression by boosting aortic wall degradation. 

In conclusion, glucose metabolism, mitochondrial function and microRNA are important pathways in the pathophysiology of AAA and promising targets for pharmacological modulation.