The goal of this study was to elucidate whether there is an increase in myocardial
tetrahydrobiopterin (BH4), which is a cofactor for
nitric oxide synthase, during the late phase of ischaemic preconditioning (IPC) leading to cardioprotection against
myocardial infarction and, if so, to examine the induction mechanisms of BH4 synthesis. Rats were preconditioned with four cycles of 3 min left main coronary artery (LCA) occlusion followed by 10 min reperfusion. Twenty-four hours later, the rats were subjected to 20 min ischaemia by LCA
ligation and 2 h reperfusion, and the
infarct size was determined by
2,3,5-triphenyltetrazolium chloride staining. The IPC protocol reduced the
infarct size, and increased the BH4 content and expression of
GTP-cyclohydrolase I (GTPCH), which is the rate-limiting
enzyme for BH4 synthesis. Administration of a GTPCH inhibitor attenuated both the reduction in
infarct size and the increase in BH4 levels. Moreover, the increase in BH4 content was reduced by administration of
catalase or a Janus
tyrosine kinase-2 (JAK2) inhibitor. These observations suggest that upregulation of BH4 synthesis in the heart contributes to an acquisition of ischaemic tolerance in late IPC, and the increase in myocardial BH4 content seems to be mediated by the induction of GTPCH via the H(2)O(2)-JAK2 pathway.