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Role of heat shock protein 90 and endothelial nitric oxide synthase during early anesthetic and ischemic preconditioning. Anesthesiology 2009 Feb;110(2):317-25

Date

02/06/2009

Pubmed ID

19194158

Pubmed Central ID

PMC2730207

DOI

10.1097/ALN.0b013e3181942cb4

Scopus ID

2-s2.0-61549089097   46 Citations

Abstract

BACKGROUND: Nitric oxide is known to be essential for early anesthetic preconditioning (APC) and ischemic preconditioning (IPC) of myocardium. Heat shock protein 90 (Hsp90) regulates endothelial nitric oxide synthase (eNOS) activity. In this study, the authors tested the hypothesis that Hsp90-eNOS interactions modulate APC and IPC.

METHODS: Myocardial infarct size was measured in rabbits after coronary occlusion and reperfusion in the absence or presence of preconditioning within 30 min of isoflurane (APC) or 5 min of coronary artery occlusion (IPC), and with or without pretreatment with geldanamycin or radicicol, two chemically distinct Hsp90 inhibitors, or N-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase NOS inhibitor. Isoflurane-dependent nitric oxide production was measured (ozone chemiluminescence) in human coronary artery endothelial cells or mouse cardiomyocytes, in the absence or presence of Hsp90 inhibitors or N-nitro-L-arginine methyl ester. Interactions between Hsp90 and eNOS, and eNOS activation, were assessed with immunoprecipitation, immunoblotting, and confocal microscopy.

RESULTS: APC and IPC decreased infarct size (by 50% and 59%, respectively), and this action was abolished by Hsp90 inhibitors. N-nitro-L-arginine methyl ester blocked APC but not IPC. Isoflurane increased nitric oxide production in human coronary artery endothelial cells concomitantly with an increase in Hsp90-eNOS interaction (immunoprecipitation, immunoblotting, and immunohistochemistry). Pretreatment with Hsp90 inhibitors abolished isoflurane-dependent nitric oxide production and decreased Hsp90-eNOS interactions. Isoflurane did not increase nitric oxide production in mouse cardiomyocytes, and eNOS was below the level of detection.

CONCLUSION: The results indicate that Hsp90 plays a critical role in mediating APC and IPC through protein-protein interactions, and suggest that endothelial cells are important contributors to nitric oxide-mediated signaling during APC.

Author List

Amour J, Brzezinska AK, Weihrauch D, Billstrom AR, Zielonka J, Krolikowski JG, Bienengraeber MW, Warltier DC, Pratt PF Jr, Kersten JR

Authors

Amie R. Billstrom Physician Assistant Emergency Medicine in the Emergency Medicine department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin




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

Anesthetics
Animals
Benzoquinones
Blood Pressure
Blotting, Western
Chromatography, High Pressure Liquid
Endothelial Cells
Enzyme Inhibitors
HSP90 Heat-Shock Proteins
Heart Rate
Immunoprecipitation
Ischemic Preconditioning, Myocardial
Lactams, Macrocyclic
Luminescence
Macrolides
Male
Microscopy, Confocal
Myocardial Infarction
Myocytes, Cardiac
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase Type III
Ozone
Rabbits
Signal Transduction
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc