The current proposal identifies a novel hormonally regulated S-nitrosylation/denitrosylation coupling loop in the pulmonary vascular endothelium. This feedback loop consists of eNOS, which is up-regulated by estrogens, and GSNO-R, which is down-regulated by androgens. These two proteins physically interact, however the impact of this interaction on pulmonary physiology and pathology is unknown. Thus, defining the subcellular location of this interaction within the endothelial cell and the influence of this relationship on local S-nitrosothiol (SNO) abundance is of paramount importance to identifying its role in normal pulmonary vascular physiology and pathology. SNOs have been implicated in the development of various pulmonary diseases, many of which display distinct gender preferences in presentation or a change in severity at puberty by unknown mechanisms. In this respect, estrogen increases SNO formation causing a compensatory increase in GSNO-R activity. Thus, increased pulmonary vascular endothelial SNO exposure without increases in GSNO-R activity, which is abnormal in male mice exposed to exogenous SNOs, produces SNO toxicity including pulmonary vascular remodeling and PH. Thus, abnormalities in GSNO-R may diminish protection of pulmonary vascular endothelium to increased eNOS activity, resulting in increased risk to develop PH. We hypothesize that SNO bioavailability in the endothelium is regulated by a hormonally regulated S-nitrosylation/denitrosylation coupling loop. This regulatory loop may be involved in the regulation of eNOS activity and SNO bioavailability within the vascular endothelium Moreover, disruption of this regulatory loop plays a role in the gender divergence seen in PH. Three hypotheses will be examined.
Aim 1 : GSNO-R and eNOS crosstalk exists within the pulmonary endothelium.
Aim 2 : Subcellular location of eNOS/GSNO-R interaction contributes to local SNO bioavailability.
Aim 3 : Disruption of this S-nitrosylation/denitrosylation regulatory loop contributes to the gender discordance seen in PH. In summary, defining the importance of the hormonal regulation of this coupling loop and its relationship to gender susceptibility of pulmonary vascular disease will enhance our knowledge on the mechanisms of male/female mediated susceptibility/protection to disease and will increase the potential to develop gender specific therapeutic agents.
S-nitrosothiol bioactivities may play an important role in the gender discordance seen in pulmonary diseases such as asthma and pulmonary hypertension. Hormone regulated S-nitrosylation/denitrosylation regulates the activity of endothelial nitric oxide synthase and S-nitrosoglutathione reductase determining local Snitrosothiol abundance. Defining the location of this interaction and the proteins involved may lead to new therapeutic targets in the treatment of these diseases.
|Zaman, Khalequz; Sawczak, Victoria; Zaidi, Atiya et al. (2016) Augmentation of CFTR maturation by S-nitrosoglutathione reductase. Am J Physiol Lung Cell Mol Physiol 310:L263-70|
|Raffay, Thomas M; Dylag, Andrew M; Di Fiore, Juliann M et al. (2016) S-Nitrosoglutathione Attenuates Airway Hyperresponsiveness in Murine Bronchopulmonary Dysplasia. Mol Pharmacol 90:418-26|
|Marozkina, Nadzeya V; Gaston, Benjamin (2015) Nitrogen chemistry and lung physiology. Annu Rev Physiol 77:431-52|
|Sawczak, Victoria; Getsy, Paulina; Zaidi, Aliya et al. (2015) Novel Approaches for Potential Therapy of Cystic Fibrosis. Curr Drug Targets 16:923-36|
|Palmer, Lisa A; Kimberly deRonde; Brown-Steinke, Kathleen et al. (2015) Hypoxia-induced changes in protein s-nitrosylation in female mouse brainstem. Am J Respir Cell Mol Biol 52:37-45|
|Sun, Yuansheng; Periasamy, Ammasi (2015) Localizing protein-protein interactions in living cells using fluorescence lifetime imaging microscopy. Methods Mol Biol 1251:83-107|
|Wallrabe, Horst; Sun, Yuansheng; Fang, Xiaolan et al. (2015) Three-color confocal FÃ¶rster (or fluorescence) resonance energy transfer microscopy: Quantitative analysis of protein interactions in the nucleation of actin filaments in live cells. Cytometry A 87:580-8|
|Marozkina, Nadzeya V; Wang, Xin-Qun; Stsiapura, Vitali et al. (2015) Phenotype of asthmatics with increased airway S-nitrosoglutathione reductase activity. Eur Respir J 45:87-97|
|Davisson, Robin L; Bates, James N; Johnson, Alan Kim et al. (2014) Effects of intracerebroventricular injections of 5-HT on systemic vascular resistances of conscious rats. Microvasc Res 95:116-23|
|Periasamy, Ammasi (2014) Advanced light microscopy. Methods 66:121-3|
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