S-Nitrosylation and the Development of Pulmonary Hypertension
Abstract
Pulmonary hypertension (PH), high blood pressure in the lungs, is a disease with no known cure. Left untreated, this disease results in right heart failure and death. The studies performed during the past four years have focused on defining the role of S-nitrosothiols in the development and progression of PH. In the pulmonary vascular endothelium, endothelial nitric oxide synthase (eNOS) activity is associated with the formation of Snitrosothiols. S-nitrosothiol catabolism is mediated, in part, through the action of S-nitrosoglutathione reductase (GSNOR). The relationship between these two enzymes to net S-nitrosothiol bioavailablity and the development of this disease is unknown. Our studies using N-acetyl cysteine as a tracer to monitor S-nitrosothiol abundance have implicated S-nitrosothiols in the development of hypoxia-induced pulmonary hypertension in male but not female C57BL6 mice. Moreover, the observed gender differences in pulmonary vascular response are due to gender differences in the activity of GSNOR. GSNOR activity in females is controlled by the hormonal regulation of eNOS. In contrast, GSNOR activity in males is negatively controlled by testosterone in an eNOS-independent manner. Lastly, smooth muscle/endothelial cell communication in resistance arteries was found to be mediated by S-nitrosylation /denitrosylation of connexin 43 (Cx 43) at the myoendothelial junction. Cx43 is constitutively S-nitrosylated on Cys 270 by eNOS and denitrosylated by GSNOR in this cellular compartment. The importance of this interaction to that of the pulmonary vascular disease is currently unknown, but suggests the importance of these post-translational modifications in the vascular response.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2011
- Accession Number
- ADA542905
Entities
People
- Lisa A. Palmer
Organizations
- University of Virginia