Sophia Jayasekera
Research Mentor: Morgan Salmon
Mentor Department: Cardiac Surgery, Medicine
Author(s): Sophia Jayasekera, Jessica Millar, Gorav Ailawadi, Morgan Salmon
Session: Session 3 (11:00 AM – 11:50 AM)
Presentation Type: Oral Presentation
Abstract
Descending thoracic aortic aneurysm (dTAA) formation is characterized by a chronic weakening and dilating of the aortic wall, smooth muscle cell migration, and changes to the extracellular matrix. The importance of cellular metabolism in the progression of dTAAs remains understudied. The Acod1/IRG1 citric acid cycle enzyme upregulates the immunometabolite itaconate and the NRF2 transcription factor pathway to exert anti-inflammatory effects during disease progression; however, the role of this pathway in dTAAS is unclear. We hypothesize that the loss of Acod/Irg1 and decreased production of itaconate and its derivatives will exacerbate dTAAs by disrupting the NRF2 pathway. Murine dTAAs were induced in male and female C57BL/6 mice (WT) and Acod1/Irg1 knockout (Acod1/Irg1 KO) mice using an elastase application model of dTAA formation (n= 7-11 per group). Aortas were harvested 14 days after aneurysm induction, and aortas were collected for immunohistochemical analysis of elastin, collagen, vascular smooth muscle cells, macrophages, neutrophils, and T cells. Male ACOD KO mice demonstrated larger AAs compared to WT controls (WT: 102% ± 17% vs. ACOD KO: 131% ± 16%; p =0.0012). Female ACOD KO mice also had larger AAs than controls (WT: 89% ± 19% vs. ACOD KO: 124% ± 13%; p < 0.0001). Separately, murine dTAAs were induced in male and female NRF2 KO mice using the dTAA elastase model, with harvest 14 days after aneurysm induction. Male NRF2 KO mice demonstrated larger AAs compared to controls (WT: 103% ± 16% vs. NRF2 KO: 135% ± 25%; p =0.0097). While female NRF2 KO mice also demonstrated larger aneurysms compared to controls (WT: 89% ± 19% vs. NRF2 KO: 131% ± 13%; p < 0.0001). These studies identify the itaconate pathway as potentially attenuating thoracic aneurysm progression, thus making the metabolite a candidate therapeutic intervention for the treatment and prevention of the condition.
