calpain and Aortic-Diseases

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.. 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.. 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.. 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.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta; Aortic Diseases; Atherosclerosis; ATP Binding Cassette Transporter 1; Calpain; Cholesterol; Cysteine Proteinase Inhibitors; Disease Models, Animal; Gene Expression Regulation; Leupeptins; Lipid Metabolism; Liver X Receptors; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Plaque, Atherosclerotic; PPAR gamma; RNA, Messenger; Scavenger Receptors, Class A

In the previous in vitro study, we found that simvastatin decreased the protein expression of CD36, the scavenger receptor, and calpain-1, the Ca2+-sensitive cysteine protease, in oxidized low-density lipoprotein (oxLDL)-treated macrophages. In this in vivo study, we investigated whether simvastatin downregulates the expression of CD36 and calpain-1 and inhibits the inflammation and atherosclerosis in apolipoprotein E knockout (ApoE KO) mice.. Twenty male 6-week-old ApoE KO mice were divided into 2 groups: the ApoE KO group and the ApoE KO + simvastatin (ApoE KO + Sim) group. Atherosclerotic lesions were evaluated and the expressions of CD68, CD36, and calpain-1 in aorta were examined.. Simvastatin inhibited the atherosclerotic lesion in ApoE KO mice. In addition, simvastatin reduced the contents of oxLDL, thiobarbituric acid reactive substances, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum, decreased the mRNA and protein expressions of CD36 and reduced the mRNA expression of TNF-α and IL-6 in the aortas. Furthermore, simvastatin reduced the calpain activity and the protein expression of calpain-1 in the aorta.. The results suggested that the attenuation of atherosclerotic lesions in ApoE KO mice by simvastatin might be associated with the downregulations of CD36 and calpain-1 and with inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Calpain; CD36 Antigens; Disease Models, Animal; Down-Regulation; Genetic Predisposition to Disease; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Inflammation Mediators; Interleukin-6; Lipoproteins, LDL; Male; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Plaque, Atherosclerotic; Simvastatin; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha