V. Shah et al., Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension, AM J P-GAST, 40(2), 1999, pp. G463-G468
Citations number
23
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
The molecular chaperone, heat shock protein 90 (Hsp90), acts as an intermed
iate in the signaling cascades leading to activation of endothelial nitric
oxide synthase (eNOS). In this study, we examine the participation of this
pathway in nitric oxide (NO)-dependent vasodilation in the rat mesentery in
vitro. In normal animals, immunoprecipitation of eNOS from intact mesenter
y coimmunoprecipitates Hsp90 and, additionally, both eNOS and Hsp90 colocal
ize to the endothelial lining of mesenteric vessels. In the perfused mesent
eric vasculature of normal animals, geldanamycin (GA), a specific inhibitor
of Hsp90 signaling, attenuates ACh-dependent vasodilation but does not aff
ect vasodilation in response to sodium nitroprusside. Next, studies were pe
rformed in animals with experimental portal hypertension induced by portal
vein ligation (PVL). In PVL animals, NOS catalytic activity is markedly enh
anced in mesenteric tissue and the perfused mesentery is hyporesponsive to
the vasoconstrictor methoxamine (MTX). GA significantly potentiates MTX-ind
uced vasoconstriction after PVL, thereby partially reversing the hyporeacti
vity to this agent exhibited in the mesenteric vasculature after PVL. These
studies suggest that Hsp90 can act as a signaling mediator of NO-dependent
responses in the mesenteric circulation and indicate that the excessive NO
production observed in portal hypertension is mediated in part through Hsp
90 signaling.