Abstract 15194: Antioxidant-1, Proinflammatory Cu-Dependent Transcription Factor, Mediates Disturbed Flow-Induced Endothelial Cell Inflammation and Atherosclerosis
Introduction: Disturbed flow (d-flow) including oscillatory shear (OS) causes endothelial dysfunction, leading to atherosclerosis. SUMOylation alters localization and transcriptional activity of protein. Copper (Cu), an essential micronutrient, plays a pivotal role in inflammation. We recently reported that Cu transport protein, antioxidant 1 (Atox1) functions not only as Cu chaperone to activate secretory Cu enzymes via Cu exporter ATP7A, but also as Cu-dependent transcription factor for inflammatory genes.
Hypothesis: Atox1 is involved in OS-induced endothelial cells (ECs) inflammation and atherosclerosis.
Results: We produced a region of d-flow in ApoE -/- mice using partial ligation of left common carotid artery (LCA) and high-fat feeding for 3 weeks. Atherosclerotic lesion (78 ±3.8%; Oil red O) were decreased in Atox1-/-/ApoE-/- mice which was associated with decreased ICAM1/VCAM1 expression (p<0.05), inflammatory cell recruitment (Mac3+) and extracellular matrix deposition (Masson trichrome) than ApoE-/- mice. Aortic EC located in d-flow exposed areas in ApoE-/- mice visualized by en face staining, and cultured ECs exposed OS (±5 dyne/cm2), but not laminar shear stress, showed increased Atox1 nuclear translocation and increased ICAM1 (3.9±1.1 fold)/VCAM1 (1.8 ± 0.3 fold) expression, which was rescued by Atox1 knockdown. Mechanistically, OS promoted Atox1 SUMOylation. Importantly, OS-induced Atox1 nuclear translocation was inhibited by SUMOylation-defective mutant Atox1-K3R, Cu chelator or Cu importer CTR1 siRNA. Furthermore, OS promoted downregulation of Cu transporter ATP7A via binding to COMMD1, a key regulator of CuATPase proteasomal degradation, thereby switching Atox1 from the Cu chaperone for ATP7A to the Cu-dependent transcription factor. Indeed, COMMD1 knockdown rescued ATP7A expression reduction (63±7.4%) and Atox1 nuclear translocation induced by OS.
Conclusion: OS-induced downregulation of ATP7A via COMMD1 promoted Atox1 nuclear translocation mediated through SUMOylation, thereby enhancing Atox1-dependent adhesion molecule expression in ECs. Thus, Atox1 is a novel Cu-dependent mechanosensitive transcription factor that senses OS-induced signal to promote EC inflammation and atherosclerosis.
Author Disclosures: S. Varadarajan: None. A. Das: None. A. Kato: None. K. Lizama: None. A. Waghulkar: None. B. Surenkhuu: None. H. Jo: None. M. Ushio-Fukai: None. T. Fukai: None.
- © 2016 by American Heart Association, Inc.