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1 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA
2 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
3 St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
4 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: bharris{at}mail.mcg.edu.
HMG-CoA reductase inhibitors, statins, provide beneficial effects independent of their lipid lowering effects. One beneficial effect appears to involve acute activation of endothelial nitric oxide synthase (eNOS) and increased nitric oxide (NO) release. However, the mechanism of acute statin-stimulated eNOS activation is unknown. Therefore, we hypothesized that eNOS activation may be coupled to altered eNOS phosphorylation. Bovine aortic endothelial cells (BAECs), passage 2-6, were treated with either lovastatin or pravastatin from 0-30 min. eNOS phosphorylation was examined by Western blot using phospho-specific antibodies for Ser-1179, Ser-635, Ser-617, Thr-497, and Ser-116. Statin-stimulation of BAECs increased eNOS phosphorylation at Ser-1179 and Ser-617 which was blocked by the PI3-kinase/Akt inhibitor, wortmannin, and at Ser-635 which was blocked by the protein kinase A (PKA) inhibitor, KT720. Statin treatment of BAECs transiently increased NO-release by 4-fold measured by cGMP accumulation and was attenuated by L-NAME, wortmannin, and KT5720, but not by mevalonate. In conclusion, these data demonstrate that eNOS is acutely activated by statins independent of HMG-CoA reductase inhibition and that in addition to Ser-1179, eNOS phosphorylation at Ser-635 and Ser-617 through PKA and Akt, respectively, may explain, in part, a mechanism by which eNOS is activated in response to acute statin treatment.
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