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Chronic hypoxia increases endothelial nitric oxide synthase generation of nitric oxide by increasing heat shock protein 90 association and serine phosphorylation. Circ Res 2002 Aug 23;91(4):300-6

Date

08/24/2002

Pubmed ID

12193462

DOI

10.1161/01.res.0000031799.12850.1e

Scopus ID

2-s2.0-0037163147   87 Citations

Abstract

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 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. Such changes in eNOS function appear to play a critical role in protecting the myocardium against ischemic injury.

Author List

Shi Y, Baker JE, Zhang C, Tweddell JS, Su J, Pritchard KA Jr

Authors

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Benzoquinones
Blotting, Western
Chronic Disease
Enzyme Activation
Enzyme Inhibitors
Fluorescent Dyes
HSP90 Heat-Shock Proteins
Hypoxia
In Vitro Techniques
Lactams, Macrocyclic
Myocardial Ischemia
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Oxidative Stress
Phosphorylation
Protein Binding
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
Quinones
Rabbits
Recovery of Function
Serine
Superoxides
Ventricular Function, Left
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