title: Atorvastatin inhibits CXCR7 induction to reduce macrophage migration.
abstract: We have recently reported that CXCR7, the alternate high affinity SDF-1 receptor, is induced during monocyte-to-macrophage differentiation, leading to increased macrophage phagocytosis linked to atherosclerosis. Statins, the most widely used medications for atherosclerosis, were shown to have pleiotropic beneficial effects independent of their cholesterol-lowering activity. This study aimed to determine whether induction of CXCR7 during macrophage differentiation is inhibited by statins and its significance on macrophage physiology. Here we show for the first time that atorvastatin dose-dependently inhibited CXCR7 mRNA and protein expression in THP-1 macrophages, without affecting the other SDF-1 receptor, CXCR4. Pharmacotherapy relevant dose of atorvastatin affected neither cell viability nor macrophage differentiation. Suppression of CXCR7 expression was completely reversed by supplementation with mevalonate. Inhibition of squalene synthase, the enzyme committed to cholesterol biosynthesis, also decreased CXCR7 induction, albeit not as efficacious as atorvastatin. However, the geranylgeranyl transferase inhibitor, GGTI-286, the farnesyl transferase inhibitor, FTI-276, and the Rho kinase inhibitor, Y-27632, all failed to mimic the effect of atorvastatin, suggesting that the protein prenylation pathways are not critical for atorvastatin inhibition of CXCR7 induction. Interestingly, the dramatic effect of atorvastatin was only partially mimicked by other statins including pravastatin, fluvastatin, mevastatin, and simvastatin. Furthermore, activation of CXCR7 by SDF-1, TC14012, or I-TAC all prompted macrophage migration, which was significantly suppressed by atorvastatin treatment, but not by the CXCR4 antagonist. We conclude that atorvastatin modulates macrophage migration by down-regulating CXCR7 expression, suggesting a new CXCR7-dependent mechanism of atorvastatin to benefit atherosclerosis treatment beyond its lipid lowering effect.
authors.affiliation: Division of Pharmacology, Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, United States.
authors.forename: Wanshu
authors.initials: W
authors.lastname: Ma
authors.affiliation: Division of Pharmacology, Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, United States.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Pharmacology, Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, United States.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Pharmacology, Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, United States.
authors.forename: Lingxin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Pharmacology, Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Crocker
authors.affiliation: Division of Pharmacology, Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, United States. Electronic address: jzs0019@auburn.edu.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shen
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002784:Cholesterol / Q000096:biosynthesis; D017931:DNA Primers; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: C501896:ACKR3 protein, human; D000924:Anticholesteremic Agents; D017931:DNA Primers; D006538:Heptanoic Acids; D011758:Pyrroles; D012333:RNA, Messenger; D054387:Receptors, CXCR; D002784:Cholesterol; D000069059:Atorvastatin
keywords: AMD3100 (PubChem CID: 65015); Atorvastatin; Atorvastatin (PubChem CID: 15378998); CXCR7; Cell migration; Chemokine receptor; Fluvastatin (PubChem CID: 446155); Macrophages; Mevalonate (PubChem CID: 5288798); Mevastatin (PubChem CID: 16760562); Pravastatin (PubChem CID: 16759173); Simvastatin (PubChem CID: 54454); Squalestatin (PubChem CID: 6438355); Y-27632 (PubChem CID: 9901617)