Hypercholesterolemia of obese mice with deletion of vascular adhesion protein-1 occurs without other atherosclerosis risk factor

Abstract

Aim: Encoded by Aoc3 gene, Vascular Adhesion Protein-1 (VAP-1), also called semicarbazide-sensitive amine oxidase (SSAO), is a protein supporting leucocyte extravasation to inflammation sites and catalyzing the oxidation of primary amines. We previously observed that a genetically-modified mouse model lacking active VAP-1/SSAO is obese and hypercholesterolemic. Here, we further studied the alterations related to factors that increase or alleviate the risk of atherosclerosis.Methods: Body weight and glucose tolerance were determined in mice homozygous for a null mutation of Aoc3 (AOC3KO) and fed standard or high-fat diet (HFD). White adipose tissue (WAT) inflammation was assessed by immunohistological observations. Cholesterol trafficking was explored by determining plasma and tissue levels and key enzyme expression. Vascular reactivity and VAP-1/SSAO activity were assessed via hydrogen peroxide release, uric acid and nitrate/nitrite levels.Results: AOC3KO mice were devoid of VAP-1/SSAO protein and activity, while, in WT control, WAT was the richest anatomical location regarding the capacity to oxidize benzylamine. AOC3KO mice were obese but did not exhibit alteration of glucose tolerance or insulin secretion. The elevated plasma cholesterol of AOC3KO mice was further increased by HFD, with LDL cholesterol levels higher than in WT. An increased cholesteryl ester accumulation occurred in plasma, liver and WAT, with higher HMGCoA expression in WAT and slightly reduced SR-BI hepatic transporters. However, in AOC3KO mice, no sign of WAT inflammation was detected, while lower hydrogen peroxide release and higher nitrite levels were found in aorta and kidney.Conclusion: The obesity of AOC3KO mice occurred with hypercholesterolemia but without other atherosclerosis risk factors, such as worsened insulin sensitivity, WAT inflammation, increased oxidative stress and reduced nitric oxide availability