Original Article
Copyright ©2010 Baishideng. All rights reserved
World J Gastroenterol. Apr 21, 2010; 16(15): 1837-1844
Published online Apr 21, 2010. doi: 10.3748/wjg.v16.i15.1837
Role of HSP-90 for increased nNOS-mediated vasodilation in mesenteric arteries in portal hypertension
Lukas Moleda, Lars Jurzik, Matthias Froh, Erwin Gäbele, Claus Hellerbrand, Rainer H Straub, Jürgen Schölmerich, Reiner Wiest
Lukas Moleda, Lars Jurzik, Matthias Froh, Erwin Gäbele, Claus Hellerbrand, Rainer H Straub, Jürgen Schölmerich, Reiner Wiest, Department of Internal Medicine I, University Medical Center, D-93042 Regensburg, Germany
Author contributions: Wiest R, Straub RH, Schölmerich J and Hellerbrand C designed the research; Moleda L, Jurzik L, Froh M and Gäbele E performed the research; Froh M and Hellerbrand C contributed analytical tools; Wiest R wrote the paper.
Supported by Grants from the German Research Association (DFG) to Wiest R; and the Medical Faculty of the University of Regensburg (ReForM) to Gäbele E, Hellerbrand C and Wiest R
Correspondence to: Reiner Wiest, MD, Department of Internal Medicine I, University Medical Center, D-93042 Regensburg, Germany. reiner.wiest@klinik.uni-regensburg.de
Telephone: +49-941-9447014 Fax: +49-941-9447016
Received: September 9, 2009
Revised: December 4, 2009
Accepted: December 11, 2009
Published online: April 21, 2010
Abstract

AIM: To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension.

METHODS: Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinephrine (EC80) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with geldanamycin (specific inhibitor of HSP-90 signalling, 3 μg/mL) or L-NAME (non-specific NOS-blocker, 10-4 mol/L).

RESULTS: nNOS and HSP-90 expression was significantly increased in mesenteric nerves from PVL as compared to sham rats. Moreover, nNOS and HSP-90 were visualized in mesenteric nerves by immunofluorescence and immunoprecipitation of nNOS co-immunoprecitated HSP-90 in sham and PVL rats. PNS induced a frequency-dependent vasorelaxation which was more pronounced in PVL as compared to sham rats. L-NAME and geldanamycin markedly reduced nNOS-mediated vasorelaxation abrogating differences between the study groups. The effect of L-NAME and geldanamycin on nNOS-mediated vasorelaxation was significantly greater in PVL than in sham animals. However, no difference in magnitude of effect between L-NAME and geldanamycin was noted.

CONCLUSION: HSP-90 acts as a signalling mediator of nNOS-dependent nerve mediated vascular responses in mesenteric arteries, and the increased nitrergic vasorelaxation observed in portal hypertension is mediated largely by HSP-90.

Keywords: Heat shock protein-90; Nitric oxide; Vasodilation; Portal hypertension; Mesenteric circulation