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

Document Type : Original Article


1 Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Objective: According to the response-to-retention hypothesis, the inception of atherosclerosis is attributed to the
deposition and retention of lipoprotein in the arterial intima, facilitated by altered proteoglycans with hyperelongated
glycosaminoglycan (GAG) chains. Recent studies have elucidated a signaling pathway whereby transforming growth
factor-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 known
to exhibit pleiotropic effects, including antioxidant and anti-inflammatory. The purpose of the present research was
to ascertain the influence of atorvastatin on TGF-β-stimulated expression of CHST11 and CHSY1 and associated
signaling pathways using an in vitro model.
Materials and Methods: In this experimental study, vascular smooth muscle cells (VSMCs) were pre-incubated
with atorvastatin (0.1-10 μM) prior to being stimulated with TGF-β (2 ng/ml). The experiment aimed to evaluate the
phosphorylation levels of Smad2C, Smad2L, ERK1/2, the NOX p47phox subunit, ROS production, and the mRNA
expression of CHST11 and CHSY1.
Results: Our research results indicated that atorvastatin inhibited TGF-β-stimulated CHSY1 and CHST11 mRNA
expression. Further experiments showed that atorvastatin diminished TGF-β-stimulated ROS production and weakened
TGF-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 modulation
of the ROS-ERK1/2-Smad2L signaling pathway. This provides valuable insight into the potential mechanisms by which
atorvastatin exerts its pleiotropic effects against atherosclerosis.


Main Subjects

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