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S-Nitrosylation and the Development of Pulmonary Hypertension

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Annual rept. 15 Jan 2009-14 Jan 2010

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Nitric oxide NO transfer reactions between protein and peptide cysteines are thought to represent a regulated signaling process. In the pulmonary endothelium, endothelial nitric oxide synthase is required for the formation of S-nitrosothiols whereas, S-nitrosoglutathione reductase GSNO-R is involved in S-nitrosothiol breakdown. Interestingly, both proteins are regulated by sex steroids eNOS activity is upregulated by estrogen and GSNO-R is downregulated by testosterone. Previous studies suggest that the differences in GSNO-R activity may be responsible for the gender dependent effects seen in our model of pulmonary hypertension. Examination of Snitrosothiol hemoglobin content in blood taken from the right ventricle from male and female C57BL6 animals show no differences, suggesting in health, the activities of eNOS and GSNO-R are balanced. Molecularly, we have determined that these two proteins interact, either directly or indirectly and treatment with an S-nitrosylating agent disrupts this interaction. In addition, both eNOS and GSNO-R are S-nitrosylated and overexpression of GSNO-R in endothelial cell culture modifies phosphorylation of eNOS serine 1177, which has been implicated in eNOS activation. Pulmonary responses to eNOS knockout mice demonstrated elevated right ventricular pressures only with SNOAC and Hypoxia. GSNOR deficient mice fail to respond to any treatment. Taken together, this suggests the existence of an Snitrosylation denitrosylation coupling loop and importance on the activity of GSNO-Reductase. Disruption of this loop may lead to the development of pulmonary disease.

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  • Medicine and Medical Research

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