Abstract 523: Phenotypic And Metabolic Switching Of Fibroblasts In Aortic Aneurysm

Background: Aortic aneurysm (AA) is a deadly cardiovascular disease that carries a tremendous burden worldwide. There are currently no approved pharmacological treatments to prevent or stop the progression of AA. Fibroblasts occupy the tunica adventitia layer of blood vessels and, during stress and in many cardiovascular diseases, fibroblasts become activated into myofibroblasts. Metabolic and mitochondrial abnormalities have also been observed in fibroblasts during various other cardiovascular diseases. The aim of this project is to assess the phenotypic and metabolic state of fibroblasts in aortic aneurysm using in vitro and in vivo murine models. Methods and Results: Aortic adventitial fibroblasts isolated from wild-type mice were used for all in vitro experiments. Angiotensin II (Ang II) was used as an in vitro inducer of fibroblast activation. Preliminary investigations suggest mitochondrial abnormalities in activated fibroblasts that ensued after in vitro Ang II treatment. Alpha smooth-muscle actin, a myofibroblast marker, was upregulated in fibroblasts following Ang II treatment. Activation of fibroblasts in response to Ang II was also associated with activation of Drp1, an inducer of mitochondrial fission. Using Seahorse extracellular flux analysis and Mitotracker Red staining, we identified alterations in mitochondrial structural and function in response to Ang II. 8-10-week-old apolipoprotein E knockout mice, implanted with micro-osmotic pumps to infuse Ang II for 4 weeks, were used to investigate the role of Drp1 in the onset and progression of AA. A subgroup of these mice received daily injections of mdivi-1. Preliminary results validate the successful generation of a murine model of TAA suitable for investigations using a pharmacological blocker of Drp1 activity. Echocardiographic assessment of aortic structure (diameter) and function (expansion index) validated the occurrence of TAA in angiotensin II-infused ApoEKO mice, which was found to be reduced in response to mdivi-1, an inhibitor of Drp1 activity, treatment. Conclusion: The results from this study could provide novel insight into the role of mitochondrial dynamics and metabolism in contributing to AA pathophysiology.