Abstract 320: Metabolic Basis Of Vascular Smooth Muscle Cell Phenotypic Switching And Atherosclerosis

Background: Phenotypic switching of vascular smooth muscle cells (VSMC) has proven to be a key contributing factor to the development of atherosclerosis. In response to pathologic stimuli, VSMCs can undergo transdifferentiation to acquire phenotypes resembling synthetic, adipogenic, osteogenic, and macrophage-like foam cells. Increased mitochondrial fission and accompanying metabolic changes are believed to promote VSMC transdifferentiation and metabolic dysfunction in vascular diseases. Dynamin-related protein 1 (Drp1) is a GTPase that mediates mitochondrial fission; the mechanistic role of Drp1 activation in each pathologic VSMC phenotype requires further investigation. In the current study, we assessed how specific post-translational modifications (PTMs) contribute to Drp1 activation and mitochondrial metabolism in transdifferentiated VSMC phenotypes. Additionally, we explored if in vivo downregulation of Drp1 ameliorated the development of atherosclerosis in the thoracic aorta. Methods and Results: Mitochondrial dynamics and cellular metabolism were assessed in transdifferentiated VSMCs. Alterations in mitochondrial morphology were evaluated using Mitrotracker red staining and TEM. To determine the role of Drp1 in VSMC phenotypic switching, phosphorylation, O-GlcNAcylation, and acetylation of Drp1 were compared between individual VSMC phenotypes. The cellular bioenergetics of each VSMC phenotype were assessed to determine differences in the OCR and ECAR. Increased Drp1 activation correlated to alterations in the bioenergetic profile and increased metabolic dysfunction in the vasculature. Using SMC-specific Drp1 knockdown murine models, we utilized echocardiography, immunofluorescence, and histological staining to illustrate if the downregulation of Drp1 ameliorated atheroma formation and reduced VSMC phenotypic switching. Conclusions: The development of atherosclerosis is multifaceted; however, evidence has indicated that Drp1-induced mitochondrial fission differs in atherosclerotic VSMC phenotypes. By comparing the mitochondrial morphology and various PTMs of Drp1 in VSMC phenotypes, we can potentially isolate “precise” therapeutic targets to mitigate the development of atherosclerosis.