Atorvastatin’s Therapeutic Potential in Atherosclerosis: Inhibiting TGF-β-Induced Proteoglycan Glycosaminoglycan Chain Elongation through ROS-ERK1/2-Smad2L Signaling Pathway Modulation in Vascular Smooth Muscle Cells

Abstract

Objective: According to the response-to-retention hypothesis, the inception of atherosclerosis is attributed to thedeposition and retention of lipoprotein in the arterial intima, facilitated by altered proteoglycans with hyperelongatedglycosaminoglycan (GAG) chains. Recent studies have elucidated a signaling pathway whereby transforming growthfactor-β (TGF-β) promotes the expression of genes linked to proteoglycan GAG chain elongation (CHSY1 and CHST11)via reactive oxygen species (ROS) and the downstream phosphorylation of ERK1/2 and Smad2L. Atorvastatin is knownto exhibit pleiotropic effects, including antioxidant and anti-inflammatory. The purpose of the present research wasto ascertain the influence of atorvastatin on TGF-β-stimulated expression of CHST11 and CHSY1 and associatedsignaling pathways using an in vitro model.Materials and Methods: In this experimental study, vascular smooth muscle cells (VSMCs) were pre-incubatedwith atorvastatin (0.1-10 μM) prior to being stimulated with TGF-β (2 ng/ml). The experiment aimed to evaluate thephosphorylation levels of Smad2C, Smad2L, ERK1/2, the NOX p47phox subunit, ROS production, and the mRNAexpression of CHST11 and CHSY1.Results: Our research results indicated that atorvastatin inhibited TGF-β-stimulated CHSY1 and CHST11 mRNAexpression. Further experiments showed that atorvastatin diminished TGF-β-stimulated ROS production and weakenedTGF-β-stimulated phosphorylation of p47phox, ERK1/2, and Smad2L; however, we observed no effect on the TGF-β-Smad2C pathway.Conclusion: These data suggest that atorvastatin demonstrates anti-atherogenic properties through the modulationof the ROS-ERK1/2-Smad2L signaling pathway. This provides valuable insight into the potential mechanisms by whichatorvastatin exerts its pleiotropic effects against atherosclerosis.

Keywords

• atorvastatin
• glycosaminoglycans
• smad proteins
• transforming growth factor