It has been shown that
geranylgeranylacetone (GGA) protects heart against
ischemia/reperfusion injury via enhanced
heat shock protein 72 (HSP72) expression in rats. In the present study, we investigated the protective effect of GGA on
ischemia/reperfusion-induced endothelial dysfunction. Rats were given oral GGA (GGA group) or vehicle (CON group), and 24 hours later their hearts were removed and placed in the Langendorff apparatus for 30-minute low-flow
ischemia followed by 30-minute reperfusion. GGA improved the postischemic functional recovery (P < 0.01), which was abolished by N-nitro-
L-arginine methyl ester (
L-NAME,
NO synthase inhibitor). NO production during both
ischemia and reperfusion were increased in the GGA group, and the
acetylcholine (ACh)-induced (endothelium-dependent) vasodilation, measured as the percentage decrease in coronary perfusion pressure after
ischemia/reperfusion (14.9 +/- 1.3%), was preserved as compared with that in the CON group (7.9 +/- 1.4%).
LY294002, a
phosphatidylinositol 3 (
PI3) kinase inhibitor, abolished the protective effects of GGA on endothelial-dependent coronary vasodilation and NO production, whereas
Y27632 (
Rho kinase inhibitor) increased endothelium-dependent coronary vasodilation and NO production in CON group toward the level seen in GGA group. The amount of
adrenomedullin in the coronary effluent at basal condition was lower in the GGA group than in the CON group (P < 0.05), and during both
ischemia and reperfusion there was no difference in the amount of
adrenomedullin between the GGA and CON groups. In addition, no difference was observed in the amount of
endothelin-1 between the GGA and CON groups. These results indicate that GGA attenuates the
ischemia/reperfusion-induced coronary endothelial dysfunction, which may contribute to its cardioprotective effect. The
PI3 kinase and/or
Rho kinase pathways appear to be involved in this process, whereas
adrenomedullin and
endothelin-1 are not necessary for the GGA-induced cardioprotection.