title: Statin post-treatment provides protection against simulated ischemia in bovine pulmonary arterial endothelial cells.
abstract: Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, can have protective effects in various organs. We determined whether application of statins after a detrimental insult protected endothelial cells. Bovine pulmonary arterial endothelial cells (BPAEC) were subjected to a 5-h oxygen-glucose deprivation (OGD) and a 1-h simulated reperfusion. Simvastatin or atorvastatin alone or plus mevalonate (the immediate product of the reaction mediated by HMG-CoA reductase), geranylgeranyl pyrophosphate (GGPP, a product downstream of mevalonate), Ly294002 (a protein kinase B/Akt inhibitor), U0126 [an extracellular signal-regulated kinase (ERK) pathway inhibitor] or diphenyleneiodonium [a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor] were added to cells immediately after the OGD for 1h. Simvastatin and atorvastatin dose-dependently reduced the OGD and simulated reperfusion-induced lactate dehydrogenase (LDH) release from primary BPAEC and BPAEC between passage 4 and 15. This effect was inhibited by mevalonate, GGPP and Ly294002 and was not affected by U0126. Consistent with those results, simvastatin and atorvastatin increased the expression of phospho-Akt/activated Akt, and did not change the expression of phospho-ERK/activated ERK after the OGD and simulated reperfusion. The OGD and simulated reperfusion-induced LDH release and superoxide production, as measured by the dihydroethidium fluorescent intensity, were inhibited by diphenyleneiodonium. These results suggest that statin post-treatment reduces OGD and simulated reperfusion-induced cell injury. This effect may be mediated by inhibiting HMG-CoA reductase and the subsequent inhibition of small GTPases. GTPase activation depends on GGPP generation and contributes to the formation of NADPH oxidase complex that produces superoxide. The statin post-treatment-induced protection may also involve activated Akt.
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.forename: Daowei
authors.initials: D
authors.lastname: Lin
authors.forename: Guofu
authors.initials: G
authors.lastname: Li
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D002417:Cattle; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007511:Ischemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D010100:Oxygen