Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
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Research Abstract |
The cardiac ATP-sensitive potassium (K_<ATP>) channel plays a crucial role in the cardioprotection induced by preconditioning. The surface channel is thought to be a complex composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit and the sulfonylurea receptor (SUR2A). Recently, although its composition has not yet been identified, the mitochondrial K_<ATP>channel has been paid attention as a key effector of preconditioning. We demonstrated prolonged myocardial ischemia specifically upregulated Kir6.1 mRNA and its protein not only in the ischemic region but also in the non-ischemic region in rat hearts. In contrast, transcriptional and protein levels for Kir6.2 and SUR2A remained unchanged. We also showed that stress-induced release of tissue Ang II is responsible for the specific induction of cardiac Kir6.1 mRNA and protein expression under myocardial ischemia. Confocal microscopic examination demonstrated Kir6.x and Kir6.1+SUR2A are non-specifically expressed in the membrane and cytosole of COS7 cells, while Kir6.x+SUR1 and Kir6.2+SUR2A are specifically expressed in the membrane alone. In contrast, none of combinations of Kir6.x+SURx are expressed in the mitochondria. We also studied the cardioprotective effects of diazoxide, a specific mitochondrial K_<ATP> channel opener, and cromakalim, a non-specific K_<ATP> channel opener in rabbits. Cromakalim, but not diazoxide, limited the infarct-size induced by prolonged myocardial ischemia. Moreover, glibenclamide, a non-specific K_<ATP> channel antagonist, inhibited the infarct-size limiting effect of preconditioning. These studies revealed that surface K_<ATP> channel composed of Kir6.2+SUR2A plays an important role in the cardioprotection. However, potential cardioprotective role of Kir6.2/Kir6.1+SUR2A needs further examination.
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