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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Pharmacology

Background:

• Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation in macrophages, forming foam cells.
• Simvastatin, an HMG-CoA reductase inhibitor, has shown potential in inhibiting atherosclerosis.
• Understanding the molecular mechanisms of simvastatin's action on macrophage foam cell formation is crucial.

Purpose of the Study:

• To investigate the effect of simvastatin on mouse peritoneal macrophage foam cell formation.
• To elucidate the underlying molecular mechanisms, focusing on the calpain-1-PPARγ-CD36 pathway.

Main Methods:

• Macrophages were treated with oxidized low-density lipoprotein (oxLDL) and simvastatin.
• Assessed cholesterol content, oxLDL uptake, inflammatory cytokine levels (TNF-α, IL-6), and gene/protein expression (CD36, PPARγ, calpain-1).
• Utilized PPARγ agonist (troglitazone) and calpain inhibitor (PD150606) to explore pathway involvement; calpain-1 overexpression was also performed.

Main Results:

• Simvastatin reduced cholesterol content and oxLDL uptake in macrophages.
• It decreased TNF-α and IL-6 levels and down-regulated CD36 and PPARγ mRNA expression.
• Simvastatin reduced calpain-1 protein expression; calpain inhibition mimicked some simvastatin effects, while calpain-1 overexpression reversed them.

Conclusions:

• Simvastatin effectively inhibits oxLDL-induced foam cell formation in macrophages.
• The mechanism involves the calpain-1-PPARγ-CD36 pathway, modulating cholesterol homeostasis and inflammation.
• These findings highlight simvastatin's therapeutic potential in atherosclerosis by targeting key cellular processes.