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1Vascular Biology Center, 2Department of Pediatrics, and 3Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912-2500; and 4Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008
Submitted 2 December 2002 ; accepted in final form 1 April 2003
Soluble guanylate cyclase (sGC) is an important downstream intracellular
target of nitric oxide (NO) that is produced by endothelial NO synthase (eNOS)
and inducible NO 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 that contain the 
- or
-subunit of sGC show that the sGC -subunit interacts directly with
HSP90 and indirectly with eNOS. Confocal immunofluorescent studies confirm the
subcellular colocalization of sGC and HSP90 in both endothelial and smooth
muscle cells. Complex formation of sGC with HSP90 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, which
is a toxic molecule that has been implicated in the pathology of several
vascular diseases.
smooth muscle cells; endothelium; vascular endothelial growth factor; bradykinin; cGMP accumulation
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