Abstract

Aims: 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.Materials and 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 52 weeks. Macitentan (30 mg/kg/day), a dual ETA/ETB receptor antagonist, was given orally for 6 weeks (27 week protocol). At sacrifice, aortas and brachiocephalic arteries (BCAs) were collected. En lace Sudan IV staining was performed on aortas and BCA sections were subjected to Masson's trichrome stain and a.-smooth muscle actin labeling.Key findings: 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.Significance: 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. (C) 2016 Elsevier Inc. All rights reserved.

Keywords

Atherosclerosis; Endothelin; Chymase; Apolipoprotein E; Macitentan

Published in

Life Sciences
2016, Volume: 159, pages: 71-75 Publisher: PERGAMON-ELSEVIER SCIENCE LTD

SLU Authors

• Pejler, Gunnar

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

Associated SLU-program

Future Animal Health and Welfare (until Jan 2017)


UKÄ Subject classification

Immunology in the medical area


Publication identifier

DOI: https://doi.org/10.1016/j.lfs.2016.03.018

Permanent link to this page (URI)

https://res.slu.se/id/publ/79421