Abstract 125: Intensive Statin Therapy Negatively Modulates AdipoR Activity in the Monocyte-macrophage Lineage in vivo and in vitro

Abstract

Introduction: Statins are widely used for primary and secondary prevention of cardiovascular disease and its complications through cholesterol lowering and anti-inflammatory effects. Adiponectin, an anti-inflammatory adipokine, acts via 2 receptors, AdipoR1 and AdipoR2, to exert protective effects on the vasculature. Recently, we demonstrated that AdipoR are highly expressed on macrophages and that decreased AdipoR2 activity is associated with atherosclerotic plaque instability. We aimed to investigate whether statins can modulate AdipoR activity in the monocyte-macrophage lineage. Methods: Blood monocytes were isolated from whole blood of patients (statin-naïve vs statin users) with severe carotid atherosclerosis by a Magnetic Cell-Sorting technique. AdipoR1 and AdipoR2 mRNA expression on circulating monocytes was determined using qRT-PCR. In vitro , THP-1 macrophages were treated for 24 or 72 hours with varying doses of atorvastatin or rosuvastatin (1μM, 10μM, 60μM) to determine the effect of statins on AdipoR activity (AMPK, PPAR-α) by qRT-PCR and Western Blot analyses. Macrophage cytokine secretion (IL-1β, IL-10, IL-6, TNF-α) was assessed by electrochemiluminescence. Results: AdipoR1 and AdipoR2 mRNA expression on circulating monocytes was significantly lower by 1.36- and 1.17-fold (P<0.05), respectively, in statin users (n=157) compared to statin-naïve patients (n=37). When analyzing by statin type and dose, only patients on high doses of atorvastatin (40-80 mg) or rosuvastatin (20-40 mg) had significantly lower AdipoR expression compared to statin-naïve patients (P<0.05). Statins effects on lowering AdipoR expression was only apparent in patients with unstable but not stable plaques. In vitro , higher doses and longer exposure of macrophages to atorvastatin or rosuvastatin resulted in a greater decrease in AdipoR mRNA expression and signalling through AMPK and PPAR-α, and greater secretion of pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α. Conclusion: In our study, intensive statin therapy resulted in negative modulation of AdipoR expression and function. Despite their known protective properties, statins may also elicit severe adverse effects, which are often associated with long-term treatment and high doses.