title: C-reactive protein/oxidised low-density lipoprotein/β2-glycoprotein I complex promotes atherosclerosis in diabetic BALB/c mice via p38mitogen-activated protein kinase signal pathway.
abstract: BACKGROUND
  The aim of this study was to investigate the effect of C-reactive protein/oxidised low-density lipoprotein/β2-glycoprotein I (CRP/oxLDL/β2GPI) complex on atherosclerosis (AS) in diabetic BALB/c mice.
  
  
  METHODS
  BALB/c mice were fed high-fat and normal diet. Eight weeks later, the mice fed with high-fat diet were injected with streptozotocin (STZ) to induce diabetes. The diabetic mice were respectively injected twice monthly with 20 μg oxLDL, 20 μg β2GPI, 40 μg oxLDL/β2GPI complex, 44 μg CRP/oxLDL/β2GPI complex, and PBS. Aortas were stained with Sudan IV to investigate lipid plaque formation. The infiltration condition of smooth muscle cells (SMCs), macrophages, and T cells in the aortas were determined by immunohistochemistry (IH). The mRNA expressions of receptors associated with lipid metabolism were quantified by real-time PCR. The phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and MKK3/6 in aorta tissues were assessed by Western blot. The expression of inflammation cytokines was evaluated by protein chip.
  
  
  RESULTS
  The lipid plaques were more extensive, the lumen area was obviously narrower, the ratio of intima and media thickness were increased, and the normal internal elastic lamia structure and endothelial cell disappeared (P < 0.05) in the oxLDL and CRP/oxLDL/β2GPI groups (P < 0.05). CRP/oxLDL/β2GPI complex dramatically promoted infiltration of SMCs, macrophages, and T cells, improved the mRNA expression of ABCA1 and ABCG1, but reduced the mRNA expression of SR-BI and CD36 and increased the phosphorylation of p38MAPK and MKK3/6 (all P < 0.05). The highest expression levels of IL-1, IL-9, PF-4, bFGF, and IGF-II were detected in the CRP/oxLDL/β2GPI group (P < 0.05).
  
  
  CONCLUSIONS
  CRP/oxLDL/β2GPI complex aggravated AS in diabetic BALB/c mice by increasing lipid uptake, the mechanism of which may be mediated by the p38MAPK signal pathway.
authors.affiliation: Department of Diabetic Nephropathy Hemodialysis, Key Laboratory of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital & Tianjin Institute of Endocrinology Tianjin Medical University, Tongan Street, Tianjin, Heping District 300070, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Sai-Jun
authors.initials: SJ
authors.lastname: Zhou
authors.forename: Chun-Jun
authors.initials: CJ
authors.lastname: Li
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Wang
authors.forename: Yun-Zhao
authors.initials: YZ
authors.lastname: Tang
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Lv
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Qiu-Ling
authors.initials: QL
authors.lastname: Xing
authors.forename: De-Min
authors.initials: DM
authors.lastname: Yu
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002097:C-Reactive Protein / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D008077:Lipoproteins, LDL / Q000494:pharmacology; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013311:Streptozocin; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D053482:beta 2-Glycoprotein I / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D008077:Lipoproteins, LDL; D053482:beta 2-Glycoprotein I; C099252:oxidized low density lipoprotein; D013311:Streptozocin; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse