Chronic Hypoxia Increases Endothelial Nitric Oxide Synthase Generation of Nitric Oxide by Increasing Heat Shock Protein 90 Association and Serine Phosphorylation

doi:10.1161/01.RES.0000031799.12850.1E

Circulation Research. 2002
Published online before print August 1, 2002, doi: 10.1161/01.RES.0000031799.12850.1E

A more recent version of this article appeared on August 23, 2002

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Submitted on January 29, 2002
Revised on July 19, 2002
Accepted on July 22, 2002

Chronic Hypoxia Increases Endothelial Nitric Oxide Synthase Generation of Nitric Oxide by Increasing Heat Shock Protein 90 Association and Serine Phosphorylation

Yang Shi ^*; John E. Baker ; Chenyang Zhang ; James S. Tweddell ; Jidong Su ; and Kirkwood A. Pritchard Jr

From the Division of Pediatric Surgery (Y.S., J.E.B., J.S., K.A.P.) and Cardiothoracic Surgery (J.S.T.), The Cardiovascular Center (Y.S., J.E.B., C.Z., K.A.P.), Free Radical Research Center (K.A.P.), and Departments of Biochemistry (J.E.B.), Physiology (C.Z.), and Pharmacology and Toxicology (K.A.P.), Medical College of Wisconsin; and the Section of Cardiothoracic Surgery (J.S.T.), Children's Hospital of Wisconsin, Milwaukee, Wis.

^* To whom correspondence should be addressed. E-mail: yangshi{at}mcw.edu.

Chronic hypoxia increases endothelial nitric oxide synthase (eNOS) production of nitric oxide (·NO) and cardioprotection in neonatal rabbit hearts. However, the mechanism by which this occurs remains unclear. Recent studies suggest that heat shock protein 90 (hsp90) alters eNOS function. In the present study, we examined the role of hsp90 in eNOS-dependent cardioprotection in neonatal rabbit hearts. Chronic hypoxia increased recovery of postischemic left ventricular developed pressure (LVDP). 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 ${approx}$ 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-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. Such changes in eNOS function appear to play a critical role in protecting the myocardium against ischemic injury.

Key words: chronic hypoxia • endothelial NOS • heat shock protein 90 • superoxide anion • nitric oxide

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