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1 Department of Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
2 Department of Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
3 Department of Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA
4 Department of Pediatrics, Northwestern University, Chicago, IL, USA
5 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
6 Department of Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: jcatrava{at}mail.mcg.edu.
Soluble guanylate cyclase (sGC) is an important downstream intracellular target of nitric oxide (NO) produced by the endothelial nitric oxide synthase (eNOS) and the inducible nitric oxide synthase (iNOS). In this study, we demonstrate that sGC exists in a complex with eNOS and heat shock protein 90 (Hsp90) in aortic endothelial cells. In addition, we show that in aortic smooth muscle cells, sGC forms a complex with Hsp90. Formation of the sGC/eNOS/Hsp90 complex is increased in response to eNOS-activating agonists in a manner that depends on Hsp90 activity. In vitro binding assays with glutathione S-transferase fusion proteins containing the 
or 
subunit of sGC show that the sGC subunit interacts directly with Hsp90 and interacts indirectly with eNOS. Confocal immunofluorescent studies confirmed the subcellular co-localization of sGC and Hsp90 in both endothelial and smooth muscle cells. Complex formation of sGC with Hsp9O facilitates responses to NO donors in cultured cells (cGMP accumulation) as well as in anesthetized rats (hypotension). These complexes likely function to stabilize sGC as well as to provide directed intracellular transfer of NO from NOS to sGC, thus preventing inactivation of NO by superoxide anion and formation of peroxynitrite, a toxic molecule that has been implicated in the pathology of several vascular diseases.
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