title: Endothelin receptor antagonist macitentan or deletion of mouse mast cell protease 4 delays lesion development in atherosclerotic mice.
abstract: OBJECTIVE
  To determine the impact of mixed endothelin receptor antagonist and mouse mast cell protease-4 (mMCP-4) in the development of atherosclerosis in the mouse model.
  
  
  METHODS
  Apolipoprotein E (ApoE) KO mice were crossed with mMCP-4 KO mice to generate ApoE/mMCP-4 double KO mice. Atherosclerosis was induced with a normal- or high-fat diet for 12, 27 or 52weeks. Macitentan (30mg/kg/day), a dual ETA/ETB receptor antagonist, was given orally for 6weeks (27week protocol). At sacrifice, aortas and brachiocephalic arteries (BCAs) were collected. En face Sudan IV staining was performed on aortas and BCA sections were subjected to Masson's trichrome stain and α-smooth muscle actin labeling.
  
  
  RESULTS
  Under normal diet, both macitentan treatment and the absence of mMCP-4 reduced the development of aortic atherosclerotic lesions in 27-week old ApoE KO mice, but mMCP-4 deletion failed to maintain this effect on 52-week old mice. Under high-fat diet (WD), macitentan, but not the absence of mMCP-4, reduced aortic lesion development in ApoE KO mice. On BCA lesions of 27-week old WD mice, macitentan treatment had a small impact while mMCP-4 deletion showed improved features of plaque stability.
  
  
  CONCLUSIONS
  These results suggest that the inhibition of mMCP-4 reduces lesion spreading in the earlier phases of atherosclerosis development and can help stabilise the more advanced plaque. Macitentan treatment was more effective to prevent lesion spreading but did not improve plaque features to the same extent.
authors.affiliation: Department of Pharmacology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Houde
authors.affiliation: Department of Pharmacology, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Louisane
authors.initials: L
authors.lastname: Desbiens
authors.affiliation: Department of Cardiology, McGill University, Montréal, QC, Canada.
authors.forename: Adel
authors.initials: A
authors.lastname: Schwertani
authors.affiliation: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Pejler
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.affiliation: Department of Pharmacology, Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address: labpdj@usherbrooke.ca.
authors.forename: Pedro
authors.initials: P
authors.lastname: D'Orléans-Juste
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D050197:Atherosclerosis / Q000473:pathology*; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011743:Pyrimidines / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D012697:Serine Endopeptidases; C066932:mast cell protease 4; C533860:macitentan
keywords: Apolipoprotein E; Atherosclerosis; Chymase; Endothelin; Macitentan