title: Apelin/APJ signaling is a critical regulator of statin effects in vascular endothelial cells--brief report.
abstract: OBJECTIVE
  The endothelial response elicited by the G-protein-coupled receptor pathway involving apelin and APJ predicts an overall vasoprotective effect. As a number of downstream endothelial targets of apelin/APJ signaling are also known to be targeted by statins (3-hydroxy-3-methyl-glutaryl [HMG]-CoA reductase inhibitors) as potential mediators of their known pleiotropic effects, we evaluated for the involvement of apelin/APJ signaling in statin endothelial effects.
  
  
  RESULTS
  We found that disruption of apelin/APJ signaling in endothelial cells leads to significantly decreased expression of Krűppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin. We found that statin-mediated induction of Krűppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin expression, as well as inhibition of monocyte-endothelial adhesion, was abrogated by concurrent apelin knockdown. Moreover, we found that statins can transcriptionally regulate APJ in a Krűppel-like factor 2-dependent manner, demonstrating the presence of a positive-feedback loop.
  
  
  CONCLUSIONS
  Our findings provide a novel mechanism by which the apelin/APJ pathway serves as a critical intermediary that links statin to its pleiotropic effects in regulating endothelial gene targets and function.
authors.affiliation: Yale University School of Medicine, Section of Cardiovascular Medicine, 300 George Street, Room 770H, New Haven, CT 06511, USA.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: McLean
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Yujung
authors.initials: Y
authors.lastname: Kang
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: G Brandon
authors.initials: GB
authors.lastname: Atkins
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Hyung J
authors.initials: HJ
authors.lastname: Chun
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D019556:COS Cells; D002448:Cell Adhesion / Q000187:drug effects; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D000077340:Fluvastatin; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C115436:APLN protein, human; C104575:APLNR protein, human; D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D005229:Fatty Acids, Monounsaturated; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C546931:THBD protein, human; D018180:Thrombomodulin; D000077340:Fluvastatin; D000068718:Rosuvastatin Calcium; D019821:Simvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III