Peroxiredoxins as Mechanosensitive Antioxidants in a Subcellular‐Specific Manner

Abstract

Atherosclerotic lesions colocalize with areas of disturbed flow in the arteries. We showed that oscillatory shear stress (OS) increases reactive oxygen species (ROS) in endothelial cells (ECs) in an NADPH oxidase-dependent manner. In contrast, laminar shear stress (LS) reduces ROS via an unknown mechanism. Peroxiredoxins (PRX) are antioxidant proteins that reduce H2O2, but their role in atherogenesis is unclear. We hypothesize that shear stress regulates ROS in ECs by controlling PRX. To test this hypothesis, mouse aortic endothelial cells (MAECs) were subjected to static, laminar, and oscillatory culture conditions. Immunoblots and immunofluorescence were used to assess the expression and localization of mammalian peroxiredoxins (PRX I-VI). Immunoblots indicated that LS upregulated PRX I, III, IV, and VI levels significantly above static controls. Immunofluorescence also showed a distinct subcellular localization of each PRX: PRX I, II, V and VI in the cytoplasm, PRX I and V in the Golgi, PRX III, IV, and V in the mitochondria, and PRX IV in the plasma membrane. These results indicate that peroxiredoxins are mechanosensitive antioxidants, removing ROS in a subcellular-specific manner. We suggest that anti-inflammatory and anti-atherogenic effects of shear stress are mediated by exquisite regulation of ROS in subcellular organelles. Supported by NIH HL67413, PO1HL075209 (HJ)