Document Detail

Increased resistance to myocardial ischemia in the Brown Norway vs. Dahl S rat: role of nitric oxide synthase and Hsp90.
MedLine Citation:
PMID:  15808839     Owner:  NLM     Status:  MEDLINE    
Hearts from Brown Norway (BN/Mcw) rats are more resistant to ischemia than hearts from Dahl S (SS/Mcw) rats. We determined whether nitric oxide (.NO) is responsible for increased cardioprotection in BN/Mcw vs. SS/Mcw hearts. Hearts from the two strains were treated with N(G)-monomethyl-L-arginine (L-NMA) or S-nitrosoglutathione (GSNO) before ischemia and reperfusion. Infarct size in untreated BN/Mcw hearts was approximately 63% less than in SS/Mcw hearts. Inhibiting NOS with L-NMA increased infarct size in BN/Mcw hearts to that observed in untreated SS/Mcw hearts but did not further increase injury in SS/Mcw hearts. The .NO donor GSNO decreased infarct size in SS/Mcw rats but had no effect on BN/Mcw hearts. Plasma and heart tissue from BN/Mcw rats contained 80% and 130% more nitrite + nitrate than that from SS/Mcw rats. These data suggest that increased .NO production protects BN/Mcw hearts from ischemic injury. Real time PCR showed no differences in NOS1, NOS2 or NOS3 isozyme transcripts in the hearts from the two strains. NOS3 was the only isozyme detected by western analysis. Both strains exhibited the same level of NOS3 and hsp90 protein expression. However, hsp90 association with NOS3 in BN/Mcw hearts was increased twofold compared with SS/Mcw hearts. Inhibiting hsp90-NOS3 interaction with geldanamycin decreased the resistance to ischemia in BN/Mcw hearts but not in SS/Mcw hearts. SS/Mcw hearts also generated three times more N(omega)-nitro-L-arginine-methylester inhibitable superoxide than BN/Mcw hearts. These findings indicate that hsp90 with NOS3 increases .NO production and decreases uncoupled NOS3 activity. We conclude increased association of hsp90 with NOS3 is a major mechanism by which BN/Mcw hearts are more resistant to ischemia than SS/Mcw hearts.
Yang Shi; William Hutchins; Hitoshi Ogawa; Chung-Che Chang; Kirkwood A Pritchard; Chenyang Zhang; Pawjai Khampang; Jozef Lazar; Howard J Jacob; Parvaneh Rafiee; John E Baker
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  38     ISSN:  0022-2828     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-05     Completed Date:  2005-09-22     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  625-35     Citation Subset:  IM    
Division of Pediatric Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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MeSH Terms
Enzyme Inhibitors / pharmacology
HSP90 Heat-Shock Proteins / metabolism*
Myocardial Ischemia / enzymology*,  metabolism
Nerve Tissue Proteins / antagonists & inhibitors,  genetics,  physiology
Nitrates / metabolism
Nitric Oxide / metabolism*
Nitric Oxide Synthase / antagonists & inhibitors,  genetics,  physiology*
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Nitrites / metabolism
RNA, Messenger / analysis,  metabolism
Rats, Inbred BN
Rats, Inbred Dahl
Species Specificity
Superoxides / metabolism
omega-N-Methylarginine / pharmacology
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/HSP90 Heat-Shock Proteins; 0/Nerve Tissue Proteins; 0/Nitrates; 0/Nitrites; 0/RNA, Messenger; 10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; 17035-90-4/omega-N-Methylarginine; EC Oxide Synthase; EC Oxide Synthase Type I; EC Oxide Synthase Type II; EC Oxide Synthase Type III; EC protein, rat; EC protein, rat; EC protein, rat

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