Ding-Yu Lee1, Tung-Lin Yang2, Yi-Hsuan Huang3, Chih-I Lee3, Li-Jing Chen3, Yu-Tsung Shih3, Shu-Yi Wei3, Wei-Li Wang3, Chih-Cheng Wu4, Jeng-Jiann Chiu5. 1. Department of Food Science, China University of Science and Technology, Taipei, Taiwan; Department of Biological Science and Technology, China University of Science and Technology, Taipei, Taiwan; Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan. 2. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan; Department of Life Sciences, National Central University, Jung-Li, Taiwan. 3. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan. 4. Department of Cardiology, Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan. 5. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan; Institute of Biomedical Engineering, National Cheng-Kung University, Tainan, Taiwan; College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan. Electronic address: jjchiu@nhri.org.tw.
Abstract
BACKGROUND AND AIMS: MicroRNA (miR)-10a is a shear-regulated miR with the lowest expression in vascular endothelial cells (ECs) in athero-susceptible regions with oscillatory shear stress (OS). The aim of this study is to elucidate the relationship between EC miR-10a and atherosclerosis and develop a hemodynamics-based strategy for atherosclerosis treatment. METHODS: A combination of in vitro flow system and in vivo experimental animals was used to examine the functional roles of EC miR-10a and its clinical applications in atherosclerosis. RESULTS: En face staining showed that EC miR-10a is down-regulated in the inner curvature (OS region) of aortic arch in rats. Co-administration with retinoic acid receptor-α (RARα)- and retinoid X receptor-α (RXRα)-specific agonists rescued EC miR-10a expression in this OS region. These effects of OS and RARα/RXRα-specific agonists on EC miR-10a expression were confirmed by the in vitro flow system, and were modulated by the RARα-histone deacetylases complex, with the consequent modulation in the downstream GATA6/vascular cell adhesion molecule (VCAM)-1 signaling cascade. Animal studies showed that miR-10a levels are decreased in both aortic endothelium of atherosclerotic lesions and blood plasma from apolipoprotein E-deficient (ApoE-/-) mice. In vivo induction of EC miR-10a by administration of RARα/RXRα-specific agonists protects ApoE-/- mice from atherosclerosis through inhibition of GATA6/VCAM-1 signaling and inflammatory cell infiltration. CONCLUSIONS: Our findings indicate that down-regulation of miR-10a in aortic endothelium and blood serum is associated with atherosclerosis, and miR-10a has potential to be developed as diagnostic molecule for atherosclerosis. Moreover, EC miR-10a induction by RARα/RXRα-specific agonists is a potential hemodynamics-based strategy for atherosclerosis treatment.
BACKGROUND AND AIMS: MicroRNA (miR)-10a is a shear-regulated miR with the lowest expression in vascular endothelial cells (ECs) in athero-susceptible regions with oscillatory shear stress (OS). The aim of this study is to elucidate the relationship between EC miR-10a and atherosclerosis and develop a hemodynamics-based strategy for atherosclerosis treatment. METHODS: A combination of in vitro flow system and in vivo experimental animals was used to examine the functional roles of EC miR-10a and its clinical applications in atherosclerosis. RESULTS: En face staining showed that EC miR-10a is down-regulated in the inner curvature (OS region) of aortic arch in rats. Co-administration with retinoic acid receptor-α (RARα)- and retinoid X receptor-α (RXRα)-specific agonists rescued EC miR-10a expression in this OS region. These effects of OS and RARα/RXRα-specific agonists on EC miR-10a expression were confirmed by the in vitro flow system, and were modulated by the RARα-histone deacetylases complex, with the consequent modulation in the downstream GATA6/vascular cell adhesion molecule (VCAM)-1 signaling cascade. Animal studies showed that miR-10a levels are decreased in both aortic endothelium of atherosclerotic lesions and blood plasma from apolipoprotein E-deficient (ApoE-/-)mice. In vivo induction of EC miR-10a by administration of RARα/RXRα-specific agonists protects ApoE-/- mice from atherosclerosis through inhibition of GATA6/VCAM-1 signaling and inflammatory cell infiltration. CONCLUSIONS: Our findings indicate that down-regulation of miR-10a in aortic endothelium and blood serum is associated with atherosclerosis, and miR-10a has potential to be developed as diagnostic molecule for atherosclerosis. Moreover, EC miR-10a induction by RARα/RXRα-specific agonists is a potential hemodynamics-based strategy for atherosclerosis treatment.
Authors: Evgeny A Zemskov; Qing Lu; Wojciech Ornatowski; Christina N Klinger; Ankit A Desai; Emin Maltepe; Jason X-J Yuan; Ting Wang; Jeffrey R Fineman; Stephen M Black Journal: Antioxid Redox Signal Date: 2019-03-19 Impact factor: 8.401