The soluble isoform of guanylate cyclase (sGC) is a heterodimer protein abundant in most tissues and the principal """"""""nitric oxide (NO) receptor"""""""", responsible for the synthesis of cGMP in response to activation by NO. Because of the labile nature of NO, the amount of biologically active NO and consequently, the degree of the NO-sGC interaction are inversely related to both the intermolecular distance between sGC and the NO synthase (NOS)-generated NO, as well as the presence of competing ligands, especially superoxide. The NO-superoxide-generated peroxynitrite is a highly reactive, toxic radical responsible for the nitration and deactivation of numerous proteins. Protein-protein interactions are important determinants of NOS activity; in particular, the association of NOS with the ubiquitous heat shock protein 90 (Hsp90) greatly enhances its activity. To date, it has been assumed that sGC exists free in the cytoplasm where it competes with other NO ligands. Contrary to this assumption, we recently discovered that sGC exists in a multi-protein complex involving at least Hsp90 and NOS (eNOS or iNOS), in both endothelial and smooth muscle cells, and that this association enhances its activity in response to either endogenous NO or nitrovasodilator-derived NO, both in vitro and in vivo. This newly discovered Hsp90-sGC complexes provide novel models for understanding the multicellular effects of NO. In the proposed studies, we will investigate the molecular mechanisms of these interactions and test the hypothesis that these new models represent physiological mechanisms aimed at improving sGC activation, maximizing the NO-sGC interaction and at reducing NO scavenging by superoxide. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070214-02
Application #
6739012
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
2003-04-17
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$321,750
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Dimitropoulou, Christiana; Drakopanagiotakis, Fotios; Catravas, John D (2007) Estrogen as a new therapeutic target for asthma and chronic obstructive pulmonary disease. Drug News Perspect 20:241-52
Wheeler, Derek S; Lahni, Patrick M; Hake, Paul W et al. (2007) The green tea polyphenol epigallocatechin-3-gallate improves systemic hemodynamics and survival in rodent models of polymicrobial sepsis. Shock 28:353-9
Antonova, Galina N; Snead, Connie M; Antonov, Alexander S et al. (2007) Nitric oxide preconditioning regulates endothelial monolayer integrity via the heat shock protein 90-soluble guanylate cyclase pathway. Am J Physiol Heart Circ Physiol 292:H893-903
Yetik-Anacak, Gunay; Catravas, John D (2006) Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascul Pharmacol 45:268-76
Wheeler, Derek S; Fisher Jr, Lyle E; Catravas, John D et al. (2005) Extracellular hsp70 levels in children with septic shock. Pediatr Crit Care Med 6:308-11

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