title: Proteomic analysis of aorta and protective effects of grape seed procyanidin B2 in db/db mice reveal a critical role of milk fat globule epidermal growth factor-8 in diabetic arterial damage.
abstract: BACKGROUND
  Atherosclerosis is one of the major complications of type 2 diabetic patients (T2DM), leading to morbidity and mortality. Grape seed procyanidin B2 (GSPB2) has demonstrated protective effect against atherosclerosis, which is believed to be, at least in part, a result of its antioxidative effects. The aim of this study is to identify the target protein of GSPB2 responsible for the protective effect against atherosclerosis in patients with DM.
  
  
  RESULTS
  GSPB2 (30 mg/kg body weight/day) were administrated to db/db mice for 10 weeks. Proteomics of the aorta extracts by iTRAQ analysis was obtained from db/db mice. The results showed that expression of 557 proteins were either up- or down-regulated in the aorta of diabetic mice. Among those proteins, 139 proteins were normalized by GSPB2 to the levels comparable to those in control mice. Among the proteins regulated by GSPB2, the milk fat globule epidermal growth factor-8 (MFG-E8) was found to be increased in serum level in T2DM patients; the serum level of MFG-E8 was positively correlated with carotid-femoral pulse wave velocity (CF-PWV). Inhibition of MFG-E8 by RNA interference significantly suppressed whereas exogenous recombinant MFG-E8 administration exacerbated atherogenesis the db/db mice. To gain more insights into the mechanism of action of MFG-E8, we investigated the effects of MFG-E8 on the signal pathway involving the extracellular signal-regulated kinase (ERK) and monocyte chemoattractant protein-1 (MCP-1). Treatment with recombinant MFG-E8 led to increased whereas inhibition of MFG-E8 to decreased expression of MCP-1 and phosphorylation of ERK1/2.
  
  
  CONCLUSIONS
  Our data suggests that MFG-E8 plays an important role in atherogenesis in diabetes through both ERK and MCP-1 signaling pathways. GSPB2, a well-studied antioxidant, significantly inhibited the arterial wall changes favoring atherogenesis in db/db mice by down-regulating MFG-E8 expression in aorta and its serum level. Measuring MFG-E8 serum level could be a useful clinical surrogate prognosticating atherogenesis in DM patients.
authors.affiliation: Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatrics, Qi-Lu Hospital of Shandong University, Jinan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Bao-ying
authors.initials: BY
authors.lastname: Li
authors.forename: Xiao-li
authors.initials: XL
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Cai
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mei
authors.initials: M
authors.lastname: Cheng
authors.forename: Mei
authors.initials: M
authors.lastname: Yin
authors.forename: Jun-fu
authors.initials: JF
authors.lastname: Wang
authors.forename: Jian-hua
authors.initials: JH
authors.lastname: Zhang
authors.forename: Wei-da
authors.initials: WD
authors.lastname: Lu
authors.forename: Rui-hai
authors.initials: RH
authors.lastname: Zhou
authors.forename: Hai-qing
authors.initials: HQ
authors.lastname: Gao
mesh_terms: D000368:Aged; D000818:Animals; D000954:Antigens, Surface / Q000097:blood / Q000378:metabolism*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D044946:Biflavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002392:Catechin / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D019295:Computational Biology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005215:Fasting / Q000097:blood; D017127:Glycation End Products, Advanced / Q000097:blood; D056604:Grape Seed Extract / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000097:blood / Q000378:metabolism*; D044945:Proanthocyanidins / Q000494:pharmacology / Q000627:therapeutic use*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D034622:RNA Interference / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D000954:Antigens, Surface; D044946:Biflavonoids; D001786:Blood Glucose; D002316:Cardiotonic Agents; D017127:Glycation End Products, Advanced; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; C098942:MFGE8 protein, human; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D044945:Proanthocyanidins; D020543:Proteome; D014280:Triglycerides; C479580:procyanidin B2; D002392:Catechin; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases