cerivastatin and Reperfusion-Injury

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.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Macrophages; Male; Microscopy, Confocal; Monocytes; Protoporphyrins; Pyridines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

Retinal ishchemia-induced neuronal death is believed to be a direct causal process in the development of many ocular diseases. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, statin, is known to improve endothelial function in proinflammatory conditions.. To investigate the effects of statin on leukocyte accumulation during ischemia-reperfusion injury and on subsequent retinal damage.. Transient retinal ischemia was induced in Long-Evans rats for 60 minutes using temporal ligation of the optic nerve. Leukocyte-endothelial interactions in the postischemic retina were evaluated in vivo with a scanning laser ophthalmoscope. Statin was administered 5 minutes before the induction of retinal ischemia. P-selectin and intercellular adhesion molecule-1 (ICAM-1) gene expression in the postischemic retina were studied with the semiquantitative polymerase chain reaction. Histologic studies were carried out to evaluate retinal damage.. The preadministration of statin attenuated the rolling and accumulation of leukocytes, decreased P-selectin and ICAM-1 expression, and reduced the number of apoptotic cells in the retina. Furthermore, histologic evaluation 168 hours after reperfusion showed that statin significantly diminished the resultant retinal tissue damage. The neuroprotective effect of statin was abolished when it was administered along with a nitric oxide synthase inhibitor, nitroglycerine-nitro-L-arginine methyl ester.. Statin may exert neuroprotective effects by inhibiting leukocyte-endothelial interaction through the release of nitric oxide from the endothelium.. As a result of its efficacy in preventing retinal neuronal death, statin may be developed into a novel therapeutic modality for many ocular ischemic diseases.

Topics: Acridine Orange; Animals; Apoptosis; Cell Adhesion; Endothelium, Vascular; Fluorescent Dyes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Situ Nick-End Labeling; Intercellular Adhesion Molecule-1; Leukocytes; Male; Neurons; Neuroprotective Agents; P-Selectin; Polymerase Chain Reaction; Pravastatin; Pyridines; Rats; Rats, Long-Evans; Reperfusion Injury; Retinal Diseases; Retinal Vessels; RNA, Messenger