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Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development
Abstract and Figures
Background: Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. Methods: Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The peroxisome proliferator-activated receptors (PPARs) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα siRNA and the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, qPCR, flow cytometry, metabolic assays, and single-cell RNA-sequencing on primary human and mouse macrophages. Results: We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity. Conclusions: This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacologic treatment for this unmet medical need.
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