1. Calpain inhibitor prevents atherosclerosis in apolipoprotein E knockout mice by regulating mRNA expression of genes related to cholesterol uptake and efflux.
- Author
-
Liu J, Wang Q, Wei Y, Zhang S, Chai E, and Tang F
- Subjects
- ATP Binding Cassette Transporter 1 genetics, ATP Binding Cassette Transporter 1 metabolism, Animals, Antigens, CD genetics, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic genetics, Antigens, Differentiation, Myelomonocytic metabolism, Aorta enzymology, Aorta pathology, Aortic Diseases enzymology, Aortic Diseases genetics, Aortic Diseases pathology, Atherosclerosis enzymology, Atherosclerosis genetics, Atherosclerosis pathology, Calpain metabolism, Disease Models, Animal, Gene Expression Regulation, Lipid Metabolism genetics, Liver X Receptors genetics, Liver X Receptors metabolism, Macrophages, Peritoneal enzymology, Macrophages, Peritoneal pathology, Male, Mice, Inbred C57BL, Mice, Knockout, ApoE, PPAR gamma genetics, PPAR gamma metabolism, Plaque, Atherosclerotic, RNA, Messenger genetics, Scavenger Receptors, Class A genetics, Scavenger Receptors, Class A metabolism, Mice, Aorta drug effects, Aortic Diseases prevention & control, Atherosclerosis prevention & control, Calpain antagonists & inhibitors, Cholesterol metabolism, Cysteine Proteinase Inhibitors pharmacology, Leupeptins pharmacology, Lipid Metabolism drug effects, Macrophages, Peritoneal drug effects, RNA, Messenger metabolism
- Abstract
Purpose: We previously reported that a calpain inhibitor (CAI) prevents the development of atherosclerosis in rats. This study aimed to investigate the effects of CAI (1 mg/kg) on atherosclerosis in apolipoprotein E knockout (ApoE KO) mice that were fed a high-fat diet (HFD) and explore the underlying mechanism by analyzing the expression of genes related to the uptake and efflux of cholesterol., Methods: Atherosclerotic plaques were evaluated. The activity of calpain in the aorta and that of superoxide dismutase (SOD) in the serum were assessed. Lipid profiles in the serum and liver were examined. Serum oxidized low-density lipoprotein (oxLDL), malondialdehyde (MDA), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) levels were measured. The mRNA expressions of CD68, TNF-α, IL-6, CD36, scavenger receptor (SR-A), peroxisome proliferator-activated receptor gamma (PPAR-γ), liver-x-receptor alpha (LXR-α), and ATP-binding cassette transporter class A1 (ABCA1) in the aorta and peritoneal macrophages were also evaluated., Results: CAI reduced calpain activity in the aorta. CAI also impeded atherosclerotic lesion formation and mRNA expression of CD68 in the aorta and peritoneal macrophages of ApoE KO mice compared with those of mice receiving HFD. However, CAI had no effect on body weight and lipid levels in both the serum and liver. CAI significantly decreased MDA, oxLDL, TNF-α, and IL-6 levels and increased SOD activity in the serum. Moreover, CAI significantly inhibited the mRNA expression of TNF-α and IL-6 genes in the aorta and peritoneal macrophages. In addition, CAI significantly downregulated the mRNA expression of scavenger receptors CD36 and SR-A and upregulated the expression of genes involved in the cholesterol efflux pathway, i.e., PPAR-γ, LXR-α, and ABCA1 in the aorta and peritoneal macrophages., Conclusions: CAI inhibited the development of atherosclerotic lesions in ApoE KO mice, and this effect might be related to the reduction of oxidative stress and inflammation and the improvement of cholesterol intake and efflux pathways., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF