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.
Gueler
Faikah
F
Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. gueler.faikah@mh-hannover.de
Park
Joon-Keun
JK
Rong
Song
S
Kirsch
Torsten
T
Lindschau
Carsten
C
Zheng
Wen
W
Elger
Marlies
M
Fiebeler
Anette
A
Fliser
Danilo
D
Luft
Friedrich C
FC
Haller
Hermann
H
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D011524:Protoporphyrins / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011524:Protoporphyrins; D011725:Pyridines; D012333:RNA, Messenger; C086276:cerivastatin; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1