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Increased resistance to myocardial ischemia in the Brown Norway vs. Dahl S rat: role of nitric oxide synthase and Hsp90. J Mol Cell Cardiol 2005 Apr;38(4):625-35

Date

04/06/2005

Pubmed ID

15808839

DOI

10.1016/j.yjmcc.2005.02.005

Scopus ID

2-s2.0-20144388473   30 Citations

Abstract

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.

Author List

Shi Y, Hutchins W, Ogawa H, Chang CC, Pritchard KA Jr, Zhang C, Khampang P, Lazar J, Jacob HJ, Rafiee P, Baker JE

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
Enzyme Inhibitors
HSP90 Heat-Shock Proteins
Myocardial Ischemia
Nerve Tissue Proteins
Nitrates
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Nitrites
RNA, Messenger
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Species Specificity
Superoxides
omega-N-Methylarginine
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a