title: Expression of type IIA secretory phospholipase A2 inhibits cholesteryl ester transfer protein activity in transgenic mice.
abstract: OBJECTIVE
  High circulating levels of group IIA secretory phospholipase A2 (sPLA2-IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet.
  
  
  RESULTS
  sPLA2-IIA expression increased atherosclerotic lesion formation in TTT compared with human apoB/human CETP double transgenic mice (P<0.01). Varespladib acid effectively inhibited plasma sPLA2-IIA activity. Surprisingly, however, administration of varespladib acid to TTT had no impact on atherosclerosis, which could be attributed to a proatherogenic plasma lipoprotein profile that appears in response to sPLA2-IIA inhibition because of increased plasma CETP activity. In the TTT model, sPLA2-IIA decreased CETP activity by reducing the acceptor properties of sPLA2-IIA-modified very low-density lipoproteins specifically because of a significantly lower apoE content. Increasing very low-density lipoprotein-apoE content by means of adenovirus-mediated gene transfer in sPLA2-IIA transgenic mice restored the acceptor properties for CETP.
  
  
  CONCLUSIONS
  These data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA2-IIA inhibition increases CETP activity via increasing the very low-density lipoprotein-apoE content, resulting in a proatherogenic lipoprotein profile.
authors.affiliation: From the Department of Bioscience, CVMD iMED, AstraZeneca, R&D, Mölndal, Sweden (E.H.-C., B.R., M.B.); Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (T.G., A.D., U.J.F.T.); INSERM UMR866, Faculté de Médecine, Université de Bourgogne, Dijon, France (T.G.); Taconic, Hudson, NY (D.S.G.); and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia (D.J.R.).
authors.forename: Eva
authors.initials: E
authors.lastname: Hurt-Camejo
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.forename: Birgitta
authors.initials: B
authors.lastname: Rosengren
authors.forename: Arne
authors.initials: A
authors.lastname: Dikkers
authors.forename: Margareta
authors.initials: M
authors.lastname: Behrendt
authors.forename: David S
authors.initials: DS
authors.lastname: Grass
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000201:enzymology / Q000235:genetics; D007211:Indoles / Q000494:pharmacology; D007651:Keto Acids; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058226:Plaque, Atherosclerotic
chemical_list: D000085:Acetates; D053318:Apolipoprotein E3; D001055:Apolipoproteins B; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D007651:Keto Acids; D008079:Lipoproteins, VLDL; C117948:varespladib; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human
keywords: apolipoproteins E; atherosclerosis; cholesterol, VLDL; cholesteryl ester transfer proteins; high-density lipoprotein cholesterol