S-Nitrosylation and the Development of Pulmonary Hypertension
Annual rept. 15 Jan 2007-14 Jan 2008
VIRGINIA UNIV CHARLOTTESVILLE
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Nitric oxide NO transfer reactions between protein and peptide cystines are thought to represent a regulated signaling process. In the current studies, N-acetyl cysteine NAC was used as a bait reactant to measure NO transfer reactions in the blood and the vascular effects of these reactions in the pulmonary vasculature. In blood, NAC was converted to S-nitroso-N acetyl cysteine SNOAC both in vivo and ex vivo. Ex vivo, SNOAC formation was found to be dependent on oxyhemoglobin desaturation. The formation of SNOAC was found to be a relatively slow K 5.3 x 10-10Ms pseudo-first order reaction. Physiologically, chronic administration of NAC resulted in the development of pulmonary hypertension that was indistinguishable from that caused by chronic hypoxia. Male endothelial nitric oxide synthase eNOS mice were protected from the effects of NAC but not SNOAC, demonstrating the importance of eNOS in this process. NAC was also found to increase the DNA binding activity of the transcription factor hypoxia inducible factor-1 HIF-1. This appears to be due, in part, by altering the interaction between HIF-1 and protein von Hippel Lindau via S-nitrosylation of cysteine 162. Together the data suggest that erythrocytic oxygen desaturation signals hypoxia through NO transfer reactions in vivo.
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