Abstract 3675: Geranylgeranylacetone, a Heat Shock Protein 90 Inducer, Improves Endothelium-Dependent Vasodilation in Forearm Circulation in Smokers though an Increases in NO Production
Background: Previous studies have shown the possibility that geranylgeranylacetone (GGA) induces expression of heat shock protein 90 (Hsp90), an adaptor molecule for assembly of endothelial nitric oxide synthase (eNOS) phosphorylation complex. Smoking is associated with impaired endothelium-dependent vasodilation. It is expected that GGA augments endothelial function through an increase in Hsp90 expression. The purpose of this study was to determine whether GGA enhances Hsp90 expression and augments endothelium-dependent vasodilation via upregulation of eNOS in smokers.
Methods and Results: We evaluated the effects of GGA on human umbilical vein endothelial cells (HUVEC) and on forearm blood flow(FBF)responses to acetylcholine (ACh) and sodium nitroprusside (SNP) in 15 healthy male smokers (27±4 yr) and 15 healthy male non-smokers (28±4 yr). FBF was measured using a mercury-filled silastic strain-gauge plethysmography. Hsp90, eNOS and Akt expression in the HUVEC and peripheral blood mononuclear cells (PBMC) was detected by Western blot analysis. ACh-induced vasodilation was smaller in the smokers than in non-smokers (10.8±4.6 vs. 14.7±5.1 mL/min/100mL, P<0.05). SNP-induced vasodilation was similar in the two groups. GGA increased Hsp90 expression and eNOS phosphorylation in HUVEC and increased Hsp90 expression in PBMC in the smokers and non-smokers. Oral administration of GGA (600 mg) augmented the FBF response to ACh form 10.8±4.6 to 19.4±7.5 mL/min/100mL (P<0.01) in smokers and from 14.7±5.1 to 25.9±8.2 mL/min/100mL (P<0.01) in non-smokers, whereas placebo did not alter the FBF response to ACh in both groups. Neither GGA nor placebo altered FBF response to SNP in both groups. Infusion of NG-monomethyl-L-arginine, an NO synthase inhibitor, completely abolished GGA-induced augmentation of the FBF response to ACh in both groups.
Conclusions: These findings suggest that induction of Hsp90 by GGA significantly increased NO-mediated vasodilatation in healthy subjects as well as smokers. GGA may indicate new therapeutic approach for improvement in endothelial dysfunction.