Thoracic aortic aneurysms (TAAs) are a common, clinically-silent dilatation of the aorta. However, complications of this disease - such as aortic dissection and rupture - are sudden and deadly. Because there is currently no validated medical therapy to prevent or reverse aortic dilation, all patients with thoracic aortic aneurysms will eventually need surgical repair. Marfan syndrome is caused by mutations in fibrillin-1, a large extracellular matrix protein responsible for elastin structure and aortic integrity. Our project proposes the use of Marfan syndrome model mice to investigate the pathogenesis of TAAs. We have shown that TAAs occur in an angiotensin receptor (AT1a receptor) dependent manner. How AT1a receptors are activated in Marfan syndrome is a gap in current knowledge. AT1a receptors are canonically activated by its main effector peptide, angiotensin II. It can also be activated in a ligand independent manner. We hypothesize that AT1a receptors in Marfan syndrome are activated in an AngII dependent manner. Furthermore, we hypothesize that depletion of endogenous AngII sufficiently attenuates TAA development in Marfan syndrome through inhibition of AT1a receptor activity. To test this hypothesis, we will determine if AngII depletion by angiotensinogen antisense oligonucleotide administration attenuates aortic dilation, aortic medial remodeling, and aortic AT1a receptor activity. We will also perform a retrospective clinical study using a large electronic health record dataset to determine if inhibition of AngII formation, angiotensin receptor blockade, or beta-blockade are associated with protection against TAA in Marfan syndrome patients. Altogether, completion of this project will provide a better understanding of the molecular mechanism behind Marfan syndrome associated thoracic aortic aneurysm pathogenesis.
Thoracic aortic aneurysms greatly increase the risk of sudden death by aortic rupture followed with rapid internal bleeding. Currently there is no validated medical therapy to treat thoracic aortic aneurysms. Uncovering the key processes which drive thoracic aortic aneurysm formation is critical for identifying targets that can modulate this disease.
