Abstract Th0031: The histone deacetylase HDAC11 contributes to diabetic vascular fibrosis

The contribution of cardiometabolic disease to atherosclerosis and other cardiovascular pathology is well described, however the mechanisms that control these pathologic changes are unclear. Although the cellular changes contributing to arterial pathology in T2D are more established in endothelial cells and vascular smooth muscle cells, there is less known about the alterations in other cell types, namely fibroblasts. Herein, using unbiased epigenetic arrays and single cell RNA-sequencing (sc-RNA-seq), we define transcriptional differences in fibroblast populations located within the adventitia of diabetic arteries that may contribute to pathologic fibrosis. We fed mice on a high fat diet to induce a diabetic state, and then utilized an unbiased epigenetic array to investigate chromatin modifying enzyme expression in whole tissue of the thoracic aortic adventitia. We identified that the histone deacetylase, Hdac11, was nearly 12-fold upregulated in vasculature of diabetic mice compared to wildtype controls (p<0.01). Next, we conducted sc-RNA-seq on infrarenal aortas of diabetic mice and wild-type controls and found that fibroblasts located within the adventitia of diabetic mice had upregulated WNT-signaling, a classic pathway for fibrosis in fibroblasts. Utilizing pathway analysis in our sc-RNA-seq dataset of infrarenal aortas, we compared fibroblasts that highly expressed Hdac11 to those that lowly expressed Hdac11 and found Hdac11 expression was positively correlated with many pro-fibrotic pathways that had shared genes with WNT-signaling, including extracellular matrix assembly and organization as well as cell-substrate adherence, among others (p<0.001). This work identifies transcriptional alterations in the fibroblasts in diabetic vascular adventitia and suggests that the histone deacetylase Hdac11 may contribute to a pro-fibrotic phenotype in diabetic arteries.