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1 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
2 Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
3 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Pediatrics, Medical College of Georgia, Augusta, GA, USA
4 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: jcatrava{at}mcg.edu.
Vascular soluble guanylate cyclase (sGC) exists in multimeric complexes with endothelial nitric oxide synthase (eNOS) and heat shock protein 90 (hsp90). Whereas disruption of hsp90-eNOS complexes clearly attenuates eNOS-depended vascular relaxation, the contribution of sGC-hsp90 complexes to eNOS- or NO donor-dependent relaxations remains unclear. Isolated rat thoracic aortic rings were pre-incubated with structurally diverse hsp90 binding inhibitors, radicicol (RA) or geldanamycin (GA) or vehicle for 0.5, 1 or 15 h. Pre-constricted vessels were exposed to ACh, 8-Br-cGMP, forskolin or one of three NO donors: nitroglycerin (NTG), sodium nitroprusside (SNP) or spermine nonoate (SNN). Both RA and GA inhibited endothelium-dependent relaxations dose-dependently. Indomethacin or the anti-oxidant tiron did not affect the inhibition of ACh-induced relaxations by GA. Long-term (15 h.) exposure to RA inhibited all NO donor-induced relaxations; however GA inhibited SNN-induced relaxation only. The effects of GA and RA appeared to be selective, because 15 h. treatment with either agent did not affect forskolin-induced relaxations, and only slightly decreased 8-Br-cGMP-induced relaxations. Similarly to their effects on NO-donor-induced relaxation, 15 h. exposure to RA, but not to GA, decreased hsp90-bound sGC protein expression and NTG-stimulated cGMP formation in aortic rings, whereas RA more than GA reduced SNN-stimulated cGMP formation. We conclude that RA, much more so than GA, selectively inhibits sGC-dependent relaxations of aortic rings by reducing sGC expression, disrupting sGC-hsp90 complex formation and decreasing cGMP formation. These studies suggest that hsp90 regulates both eNOS- and sGC- dependent relaxations.
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