title: Retinol binding protein 4 induces mitochondrial dysfunction and vascular oxidative damage.
abstract: OBJECTIVE
  Mitochondrial dysfunction has been implicated in cardiovascular diseases. Elevation of serum retinol binding protein 4 (RBP4) in patients has been linked to cardiovascular disease. However, the role of RBP4 on mitochondrial oxidative stress and vascular oxidative damage is not well demonstrated. Therefore, we evaluated the impact of RBP4 on the mitochondrial reactive oxygen species (ROS) and dynamics in the pathogenesis of cardiovascular diseases.
  
  
  RESULTS
  RBP4 treatment increased mitochondrial superoxide generation in a dose-dependent manner in human aortic endothelial cells (HAECs). Exposure to RBP4 also promoted mitochondrial dysfunction as determined by decreased mitochondrial content and integrity as well as membrane potential in HAECs. Incubation with RBP4 suppressed mitofusin (Mfn)-1 protein expression, but enhanced dynamin-related protein-1 (Drp1) and fission-1 (Fis1) protein expression in HAECs, suggesting an impairment of mitochondrial fusion and fission dynamics. Moreover, RBP4 treatment significantly induced endothelial apoptosis, increased the expression of Cytochrome C and Bax, but decreased the expression of Bcl-2. Furthermore, RBP4 stimulation suppressed phosphatidyl inositol 3-kinase (PI3K)/Akt signaling in HAECs. Finally, RBP4-Tg mice exhibited severe mitochondrial dysfunction and vascular oxidative damage in aorta compared with wide-type C57BL/6J mice.
  
  
  CONCLUSIONS
  The present study uncovers a novel mechanism through which RBP4 induces vascular oxidative damage and accelerates the development of atherosclerosis.
authors: Guangdong Provincial Key Laboratory of Food, Nutrition and Health, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China.
authors: Jingjing
authors: J
authors: Wang
authors: Guangdong Provincial Key Laboratory of Food, Nutrition and Health, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China.
authors: Hongen
authors: H
authors: Chen
authors: Guangdong Provincial Key Laboratory of Food, Nutrition and Health, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China.
authors: Yan
authors: Y
authors: Liu
authors: Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China.
authors: Wenjing
authors: W
authors: Zhou
authors: Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China.
authors: Ruifang
authors: R
authors: Sun
authors: Guangdong Provincial Key Laboratory of Food, Nutrition and Health, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. Electronic address: xiamin@mail.sysu.edu.cn.
authors: Min
authors: M
authors: Xia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D034281:Dynamins; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C000595707:BCL2 protein, human; C476525:FIS1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D045304:Cytochromes c; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Endothelial cells; Mitochondrial dysfunction; ROS; Retinol binding protein 4