S-Nitrosylation and the Development of Pulmonary Hypertension
Abstract
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 10-10M/s) 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2008
- Accession Number
- ADA482123
Entities
People
- Lisa A. Palmer
Organizations
- University of Virginia