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Role of tetrahydrobiopterin in resistance to myocardial ischemia in Brown Norway and Dahl S rats. Am J Physiol Heart Circ Physiol 2009 Nov;297(5):H1783-91



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2-s2.0-70350464515   11 Citations


Previously we showed that Brown Norway (BN/Mcw) rats are more resistant to myocardial ischemia-reperfusion (I/R) injury than Dahl S (SS/Mcw) rats due to increased nitric oxide (x NO) generation secondary to increased heat shock protein 90 (HSP90) association with endothelial nitric oxide synthase (NOS3). Here we determined whether increased resistance to I/R injury in BN/Mcw hearts is also related to tetrahydrobiopterin (BH(4)) and GTP cyclohydrolase I (GCH-1), the rate-limiting enzyme for BH(4) synthesis. We observed that BH(4) supplementation via sepiapterin (SP) and inhibition of GCH-1 via 2,4-diamino-6-hydroxypyrimidine (DAHP) differentially modulate cardioprotection and that SP alters the association of HSP90 with NOS3. BH(4) levels were significantly higher and 7,8-dihydrobiopterin (BH(2)) levels were significantly lower in BN/Mcw than in SS/Mcw hearts. The BH(4)-to-BH(2) ratio in BN/Mcw was more than two times that in SS/Mcw hearts. After I/R, BH(4) decreased and BH(2) increased in hearts from both strains compared with their preischemia levels. However, the increase in BH(2) in SS/Mcw hearts was significantly higher than in BN/Mcw hearts. Real-time PCR revealed that BN/Mcw hearts contained more GCH-1 transcripts than SS/Mcw hearts. SP increased recovery of left ventricular developed pressure (rLVDP) following I/R as well as decreased superoxide (O(2)(x-)) and increased x NO in SS/Mcw hearts but not in BN/Mcw hearts. DAHP decreased rLVDP as well as increased O(2)(x-) and decreased x NO in BN/Mcw hearts compared with controls but not in SS/Mcw hearts. SP increased the association of HSP90 with NOS3. These data indicate that BH(4) mediates resistance to I/R by acting as a cofactor and enhancing HSP90-NOS3 association.

Author List

An J, Du J, Wei N, Xu H, Pritchard KA Jr, Shi Y


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

Disease Models, Animal
Enzyme Inhibitors
GTP Cyclohydrolase
Gene Expression Regulation, Enzymologic
HSP90 Heat-Shock Proteins
Myocardial Ischemia
Myocardial Reperfusion Injury
Myocytes, Cardiac
Nitric Oxide
Nitric Oxide Synthase Type III
RNA, Messenger
Rats, Inbred BN
Rats, Inbred Dahl
Species Specificity
Ventricular Function, Left
Ventricular Pressure
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a