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• W4312638045 abstract "Background Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory arterial disorder of women with unknown etiology characterized by distorted vasculature, turbulent blood flow, and increased risk of stroke. We use platelets as an easily accessible circulating biosensor to garner mechanistic insight into FMD. Methods Thrombotic outcomes in patients with FMD were determined by multivariate regression analysis of 105,887 patients. Isolated platelets were assessed for activation by FACS and aggregometry. Single-cell (platelet) transcriptomics, proteomics, and metabolomics in FMD and healthy control platelets were performed. Platelet bioenergetics were evaluated by Seahorse and metabolic studies. Mitochondrial function, reactive oxygen species (ROS) generation, and markers of apoptosis were assessed via FACS. Results Long-term aspirin therapy in FMD is paradoxically an independent risk factor for acute ischemic stroke (OR 1.64 95% CI 1.29-1.64). Ex vivo phenotyping of FMD platelets displayed hypo-reactive responses to agonists through the P2Y12, thromboxane, protease-activated receptor 1 and collagen receptors. Integrated pathway analysis and -omics fusion revealed mitochondrial dysfunction in FMD. Seahorse analyses showed mitochondrial dysfunction present in both platelets and white blood cells in FMD patients but not in healthy individuals. FMD platelets had enhanced ROS generation compared to controls, which was ameliorated by use of mitochondrial-targeted antioxidants. Mitochondrial membrane potential, permeability transition pore gating, and Annexin V were significantly deranged in FMD platelets. Conclusions Through use of physiologic assays and interrogation of the circulating platelet transcriptome, proteome, and metabolome we reveal a hitherto unknown mitochondrial disorder in FMD, which may be exploited for therapeutic intervention. Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory arterial disorder of women with unknown etiology characterized by distorted vasculature, turbulent blood flow, and increased risk of stroke. We use platelets as an easily accessible circulating biosensor to garner mechanistic insight into FMD. Thrombotic outcomes in patients with FMD were determined by multivariate regression analysis of 105,887 patients. Isolated platelets were assessed for activation by FACS and aggregometry. Single-cell (platelet) transcriptomics, proteomics, and metabolomics in FMD and healthy control platelets were performed. Platelet bioenergetics were evaluated by Seahorse and metabolic studies. Mitochondrial function, reactive oxygen species (ROS) generation, and markers of apoptosis were assessed via FACS. Long-term aspirin therapy in FMD is paradoxically an independent risk factor for acute ischemic stroke (OR 1.64 95% CI 1.29-1.64). Ex vivo phenotyping of FMD platelets displayed hypo-reactive responses to agonists through the P2Y12, thromboxane, protease-activated receptor 1 and collagen receptors. Integrated pathway analysis and -omics fusion revealed mitochondrial dysfunction in FMD. Seahorse analyses showed mitochondrial dysfunction present in both platelets and white blood cells in FMD patients but not in healthy individuals. FMD platelets had enhanced ROS generation compared to controls, which was ameliorated by use of mitochondrial-targeted antioxidants. Mitochondrial membrane potential, permeability transition pore gating, and Annexin V were significantly deranged in FMD platelets. Through use of physiologic assays and interrogation of the circulating platelet transcriptome, proteome, and metabolome we reveal a hitherto unknown mitochondrial disorder in FMD, which may be exploited for therapeutic intervention." @default.
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• W4312638045 date "2022-01-01" @default.
• W4312638045 modified "2023-09-25" @default.
• W4312638045 title "3034 – PLATELETS AS A BIOSENSOR OF DYSFUNCTIONAL METABOLISM & BIOENERGETICS IN FIBROMUSCULAR DYSPLASIA" @default.
• W4312638045 doi "https://doi.org/10.1016/j.exphem.2022.07.090" @default.
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