Intensive statin therapy compromises the adiponectin-adipor pathway in the human monocyte-macrophage lineage

Abstract

Background and Purpose-Statins are widely used for cardiovascular disease prevention through cholesterol-lowering andanti-inflammatory effects. Adiponectin, an anti-inflammatory adipokine, acts via two receptors, AdipoR1 and AdipoR2,to exert atheroprotective effects on the vasculature. We investigated whether statins can modulate the adiponectin-AdipoRpathway in the human monocyte-macrophage lineage.Methods-Monocytes were isolated from the whole blood of patients with severe carotid atherosclerosis (cross-sectionalstudy) or from patients with cardiovascular risk factors (longitudinal study) and assessed for AdipoR1 and AdipoR2gene expression using quantitative real-time polymerase chain reaction. In vitro, THP-1 (Tamm-Horsfall protein 1)macrophages were treated with increasing atorvastatin or rosuvastatin doses for 24- or 72-hours to determine the effectof statins on AdipoR expression and activity. Macrophage cytokine secretion (IL [interleukin]-1ß, IL-10, IL-6, and TNF[tumor necrosis factor]-a) was assessed by electrochemiluminescence.Results-AdipoR1 and AdipoR2 mRNA expression on circulating monocytes from patients with carotid atherosclerosis, wassignificantly lower by 1.36- and 1.17-fold, respectively, in statin users versus statin-naïve patients. Specifically, patientson high doses of atorvastatin (40-80 mg) or rosuvastatin (20-40 mg) had significantly lower AdipoR gene expressionversus statin-naïve patients. Similarly, in the longitudinal in vivo study, longer atorvastatin/rosuvastatin treatment (=5months) in patients with cardiovascular risk factors resulted in lower AdipoR gene expression on circulating monocytesversus prestatin levels. In vitro, higher statin doses and longer exposure resulted in a greater decrease in AdipoR mRNAexpression and greater macrophage secretion of pro-inflammatory cytokines, IL-1ß, IL-6, and TNF-a. High statin dosesalso reduced adiponectin's capacity to suppress intracellular cholesteryl ester levels in oxLDL (oxidized LDL)-loadedmacrophages, with rosuvastatin exhibiting higher potency than atorvastatin.Conclusions-Our in vivo and in vitro studies identified a novel pleiotropic property of statins in modulating the adiponectinAdipoR pathway in the human monocyte-macrophage lineage, where intensive statin therapy compromised the expressionand function of adiponectin and its receptors.Visual Overview-An online visual overview is available for this article.