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1 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
2 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, United States
3 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, United States
* To whom correspondence should be addressed. E-mail: gantonova{at}mcg.edu.
Large (pathological) amounts of NO induce cell injury, whereas low (physiological) NO concentrations often ameliorate cell injury. We tested the hypotheses that pretreatment of endothelial cells (EC) with low concentrations of NO (preconditioning) would prevents injury induced by high NO concentrations. Apoptosis, induced in bovine aortic endothelial cells (BAEC) by exposing them to either 4mM sodium nitroprusside (SNP) or 0.5mM spermine NONOate for 8 hours, was abolished by 24 hour pretreatment with either 100µM SNP, 10µM spermine NONOate or 100µM 8-Br-cGMP. Repair of BAEC following wounding, measured as the recovery rate of transendothelial electrical resistance, was delayed by 8-hour exposure to 4mM SNP and this delay was significantly attenuated by 24-hour pretreatment with 0.1mM SNP. NO preconditioning produced increased association and expression of soluble guanyl cyclase (sGC) and hsp90. The protective effect of NO preconditioning, but not the injurious effect of 4mM SNP, was abolished by either a sGC activity inhibitor (ODQ) or a hsp90 binding inhibitor (radicicol) and was mimicked by 8-Br-cGMP. We conclude that preconditioning with a low dose of NO donor accelerates repair and maintains endothelial integrity via a mechanism that includes the hsp90/sGC pathway. Hsp90/sGC may thus play a role in the protective effects of NO-generating drugs from injurious stimuli.
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