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(American Journal of Pathology. 2007;170:1192-1199.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060782

Statins Attenuate Ischemia-Reperfusion Injury by Inducing Heme Oxygenase-1 in Infiltrating Macrophages

Faikah Gueler*, Joon-Keun Park*, Song Rong*, Torsten Kirsch*, Carsten Lindschau*, Wen Zheng*, Marlies Elger*, Anette Fiebeler{dagger}, Danilo Fliser*, Friedrich C. Luft{dagger} and Hermann Haller*

From the Department of Internal Medicine-Nephrology,* Hannover Medical School, Hannover; and the Franz Volhard Clinic HELIOS Klinikum-Berlin and Max Delbrück Center of Molecular Medicine,{dagger} Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany

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.




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