Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages

Statins induce heme oxygenase-1 (HO-1) in several cell types, such as vascular smooth muscle cells, endothelial cells, and macrophages. The present study assessed the role of statin-induced HO-1 up-regulation on circulating monocytes/macrophages and their contribution in preventing renal ischemia-reperfusion (IR) injury in a rat model. Cerivastatin was administered via gavage (0.5 mg/kg) for 3 days before IR injury; controls received vehicle. Statin pretreatment reduced renal damage and attenuated renal dysfunction (P < 0.05) after IR injury. The protective statin pretreatment effect was completely abolished by cotreatment with tin protoporphyrin IX (Sn-PP), a competitive HO inhibitor. IR increased HO-1 expression at the transcript and protein level in renal tissue. This effect was significantly more evident (P < 0.05) in the statin-pretreated animals 24 hours after IR injury. We identified infiltrating macrophages as the major source of tissue HO-1 production. Moreover, in ancillary cell culture (monocyte cell line) and in in vivo experiments (isolation of circulating monocytes), we confirmed that statins regulate HO-1 expression in these cells. We conclude that statin treatment up-regulates HO-1 in circulating monocytes/macrophages in vivo and in vitro. We hypothesize that local delivery of HO-1 from infiltrating macrophages exerts anti-inflammatory effects after IR injury and thereby may reduce tissue destruction.