Simvastatin inhibited oxLDL-induced proatherogenic effects through calpain-1-PPARγ-CD36 pathway.

Abstract

We previously reported that simvastatin, an inhibitor of HMG-CoA reductase, inhibits atherosclerosis in rats. The present study was designed to investigate the effect of simvastatin on mouse peritoneal macrophage foam cell formation, the early feature of atherosclerosis, and explore its mechanisms. The results showed that simvastatin decreased cholesterol content and DiI-oxLDL (1,1'-didodecyl 3,3,3',3'-indocarbocyanine perchlorate - oxidized low-density lipoprotein) uptake, reduced the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the medium, down-regulated the mRNA and protein expression of CD36 (a fatty acid receptor), and reduced the mRNA expressions of peroxisome proliferator-activated receptor gamma (PPARγ), TNF-α, and IL-6 in macrophages treated with oxLDL. However, PPARγ agonist troglitazone partly abolished the effects of simvastatin on foam cells. In addition, simvastatin reduced the protein expression of calpain-1, a Ca2+-sensitive cysteine protease, in oxLDL-treated macrophages. Furthermore, PD150606, a specific calpain inhibitor, reduced mRNA expressions of PPARγ and CD36 in macrophages treated with oxLDL. Combination of simvastatin and PD150606 had no further effect on mRNA expression of PPARγ and CD36 compared with either alone. However, over-expression of calpain-1 in macrophages partly reversed the simvastatin effects, including cell cholesterol content, mRNA expressions of PPARγ, and CD36. The results suggested that simvastatin inhibits foam cell formation of oxLDL-treated macrophages through a calpain-1-PPARγ-CD36 pathway.

• Authors: Xueyan Yang, Meihui Yin, Lan Yu, Meili Lu, Hongxin Wang, Futian Tang, Yingjie Zhang
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 94 Issue 12 Pg. 1336-1343 (Dec 2016) ISSN: 1205-7541 [Electronic] Canada
• PMID: 27733051 (Publication Type: Journal Article)

Chemical References

• CD36 Antigens
• Lipoproteins, LDL
• PPAR gamma
• oxidized low density lipoprotein
• Simvastatin
• Calpain

Topics

• Animals
• Atherosclerosis (metabolism, prevention & control)
• CD36 Antigens (antagonists & inhibitors, metabolism)
• Calpain (antagonists & inhibitors, metabolism)
• Cells, Cultured
• Humans
• Lipoproteins, LDL (antagonists & inhibitors, metabolism)
• Macrophages (drug effects, metabolism)
• Mice
• PPAR gamma (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects, physiology)
• Simvastatin (pharmacology, therapeutic use)