title: Atorvastatin inhibits CD68 expression in aortic root through a GRP78-involved pathway.
abstract: OBJECTIVE
  Glucose-regulated protein 78 (GRP78) is a chaperone protein in the endoplasmic reticulum (ER). Previous studies have suggested that statins favorably affect ER stress by upregulating GRP78. This study was designed to investigate whether the anti-atherosclerotic effect of atorvastatin is modulated by a GRP78-involved pathway.
  
  
  METHODS
  Hamsters were made diabetic and randomly divided into a diabetic control group (DMC), a diabetic group with low-dose atorvastatin (DML, 2.5 mg/kg/day), and a diabetic group with high-dose atorvastatin (DMH, 5 mg/kg/day). Pathological examinations of the aortic root were performed, and the level of GRP78 and CD68 expression in the aortic root was detected by immunohistochemistry and RT-PCR analysis. In vitro THP-1 macrophages were treated with glucose and atorvastatin, and their GRP78 and CD68 protein expression levels were measured by Western blot. Next, with and without co-incubation with the GRP78 inhibitor, deoxynivalenol (DON), CD68 protein expression was again analyzed.
  
  
  RESULTS
  We found that in vivo atorvastatin prominently limited the area of macrophage infiltration in the subendothelial spaces of the aortic root in the DML and DMH groups, and significantly inhibited CD68 expression (DML or DMH vs. DMC, all p < 0.001) and increased GRP78 expression (DML or DMH vs. DMC, p < 0.05 ~ 0.001). In vitro Western blot results showed that atorvastatin decreased CD68 and increased GRP78 protein expression in glucose-treated THP-1 macrophages, and the suppressing effect of atorvastatin on CD68 expression was almost abolished by co-incubation with the GRP78 inhibitor.
  
  
  CONCLUSIONS
  Our results clearly showed that atorvastatin inhibited CD68 expression through GRP78 regulation, and that GRP78 could exert a protective effect in the early stages of atherosclerosis beyond being a chaperone protein, providing a new perspective into the anti-atherosclerosis mechanism of atorvastatin.
authors.affiliation: Peking Union Medical College Hospital, Beijing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Chen
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yan
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D000069059:Atorvastatin; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014255:Trichothecenes / Q000494:pharmacology; D000097382:CD68 Molecule
chemical_list: D000924:Anticholesteremic Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000069059:Atorvastatin; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose; D006360:Heat-Shock Proteins; D006538:Heptanoic Acids; D011758:Pyrroles; D014255:Trichothecenes; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000717247:HSPA5 protein, human; C007262:deoxynivalenol