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Am J Physiol Heart Circ Physiol 297: H1783-H1791, 2009. First published August 28, 2009; doi:10.1152/ajpheart.00364.2009
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Role of tetrahydrobiopterin in resistance to myocardial ischemia in Brown Norway and Dahl S rats

Jianzhong An,1,2,3 Jianhai Du,1,2,3 Na Wei,1,2,4 Hao Xu,1,2,3 Kirkwood A. Pritchard, Jr.,1,2,3 and Yang Shi1,2,3

1Department of Pediatric Surgery, 2Children's Research Institution, and 3Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and 4Qilu Hospital of Shandong University, China

Submitted April 14, 2009 ; accepted in final form August 27, 2009

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 (·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 (BH4) and GTP cyclohydrolase I (GCH-1), the rate-limiting enzyme for BH4 synthesis. We observed that BH4 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. BH4 levels were significantly higher and 7,8-dihydrobiopterin (BH2) levels were significantly lower in BN/Mcw than in SS/Mcw hearts. The BH4-to-BH2 ratio in BN/Mcw was more than two times that in SS/Mcw hearts. After I/R, BH4 decreased and BH2 increased in hearts from both strains compared with their preischemia levels. However, the increase in BH2 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 (O2•–) and increased·NO in SS/Mcw hearts but not in BN/Mcw hearts. DAHP decreased rLVDP as well as increased O2•– and decreased·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 BH4 mediates resistance to I/R by acting as a cofactor and enhancing HSP90-NOS3 association.

nitric oxide; cardioprotection; guanosine 5'-triphosphate cyclohydrolase I


Address for reprint requests and other correspondence: Y. Shi, Dept. of Pediatric Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (e-mail: yangshi{at}mcw.edu).






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