title: C-reactive protein promotes atherosclerosis by increasing LDL transcytosis across endothelial cells.
abstract: OBJECTIVE
  The retention of plasma low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Whether or not C-reactive protein (CRP) can directly affect the transcytosis of LDL is not clear. Here we have examined the effect of CRP on transcytosis of LDL across endothelial cells and have explored the underlying mechanisms.
  
  
  METHODS
  Effects of CRP on transcytosis of FITC-labelled LDL were examined with human umbilical vein endothelial cells and venous rings in vitro and, in vivo, ApoE(-/-) mice. Laser scanning confocal microscopy, immunohistochemistry and Oil Red O staining were used to assay LDL.
  
  
  RESULTS
  CRP increased transcytosis of LDL. An NADPH oxidase inhibitor, diphenylene iodonium, and the reducing agent, dithiothreitol partly or completely blocked CRP-stimulated increase of LDL transcytosis. The PKC inhibitor, bisindolylmaleimide I and the Src kinase inhibitor, PP2, blocked the trafficking of the molecules responsible for transcytosis. Confocal imaging analysis revealed that CRP stimulated LDL uptake by endothelial cells and vessel walls. In ApoE(-/-) mice, CRP significantly promoted early changes of atherosclerosis, which were blocked by inhibitors of transcytosis.
  
  
  CONCLUSIONS
  CRP promoted atherosclerosis by directly increasing the transcytosis of LDL across endothelial cells and increasing LDL retention in vascular walls. These actions of CRP were associated with generation of reactive oxygen species, activation of PKC and Src, and translocation of caveolar or soluble forms of the N-ethylmaleimide-sensitive factor attachment protein.
authors: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors: Fang
authors: F
authors: Bian
authors: Xiaoyan
authors: X
authors: Yang
authors: Fan
authors: F
authors: Zhou
authors: Pin-Hui
authors: PH
authors: Wu
authors: Shasha
authors: S
authors: Xing
authors: Gao
authors: G
authors: Xu
authors: Wenjing
authors: W
authors: Li
authors: Jiangyang
authors: J
authors: Chi
authors: Changhan
authors: C
authors: Ouyang
authors: Yonghui
authors: Y
authors: Zhang
authors: Bin
authors: B
authors: Xiong
authors: Yongsheng
authors: Y
authors: Li
authors: Tao
authors: T
authors: Zheng
authors: Dan
authors: D
authors: Wu
authors: Xiaoqian
authors: X
authors: Chen
authors: Si
authors: S
authors: Jin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D002097:C-Reactive Protein / Q000008:administration & dosage / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019163:Reducing Agents / Q000494:pharmacology; D013997:Time Factors; D057900:Transcytosis / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D019163:Reducing Agents; D002097:C-Reactive Protein; D019061:src-Family Kinases; D011493:Protein Kinase C; D052066:N-Ethylmaleimide-Sensitive Proteins; C498733:Nsf protein, mouse
keywords: C-reactive protein; LDL; PKC; ROS; Src; atherosclerosis; caveolae; endothelial cells; transcytosis