TRIP

Chronic hypoxia increases endothelial nitric oxide synthase generation of nitric oxide by increasing heat shock protein 90 association and serine phosphorylation.

Circulation Research, 2002

Chronic hypoxia increases endothelial nitric oxide synthase generation of nitric oxide by increasing heat shock protein 90 association and serine phosphorylation.
yangshi@mcw.edu Chronic hypoxia increases endothelial nitric oxide synthase (eNOS) production of nitric oxide (*NO) and cardioprotection in neonatal rabbit hearts.
In the present study, we examined the role of hsp90 in eNOS-dependent cardioprotection in neonatal rabbit hearts.
Geldanamycin (GA), which inhibits hsp90 and increases oxidative stress, decreased functional recovery in normoxic and hypoxic hearts.
To determine if a loss in *NO, afforded by GA, decreased recovery, GA-treated hearts were perfused with S-nitrosoglutathione (GSNO) as a source of *NO.
GSNO increased recovery of postischemic LVDP in GA-treated normoxic and hypoxic hearts to baseline levels.
Although chronic hypoxia decreased phosphorylated eNOS (S1177) levels by approximately 4- to 5-fold and total Akt and phosphorylated Akt by 4- and 5-fold, it also increased hsp90 association with eNOS by more than 3-fold.
Using hydroethidine (HEt), a fluorescent probe for superoxide, we found that hypoxic hearts contained less ethidine (Et) staining than normoxic hearts.
Normoxic hearts generated 3 times more superoxide by an N(omega)-nitro-L-arginine methyl ester (L-NAME)-inhibitable mechanism than hypoxic hearts.
Taken together, these data indicate that the association of hsp90 with eNOS is important for increasing *NO production and limiting eNOS-dependent superoxide anion generation.