Ischemic preconditioning-mediated restoration of membrane dystrophin during reperfusion correlates with protection against contraction-induced myocardial injury.
Dystrophin is an integral membrane protein involved in the stabilization of the sarcolemmal membrane in cardiac muscle. We hypothesized that the loss of membrane dystrophin during ischemia and reperfusion is responsible for contractile force-induced myocardial injury and that cardioprotection afforded by ischemic preconditioning (IPC) is related to the preservation of membrane dystrophin. Isolated and perfused rat hearts were subjected to 30 min of global ischemia, followed by reperfusion with or without the contractile blocker 2,3-butanedione monoxime (BDM). IPC was introduced by three cycles of 5-min ischemia and 5-min reperfusion before the global ischemia. Dystrophin was distributed exclusively in the membrane of myocytes in the normally perfused heart but was redistributed to the myofibril fraction after 30 min of ischemia and was lost from both of these compartments during reperfusion in the presence or absence of BDM. The loss of dystrophin preceded uptake of the membrane-impermeable Evans blue dye by myocytes that occurred after the withdrawal of BDM and was associated with creatine kinase release and the development of contracture. Although IPC did not alter the redistribution of membrane dystrophin induced by 30 min of ischemia, it facilitated the restoration of membrane dystrophin during reperfusion. Also, myocyte necrosis was not observed when BDM was withdrawn after complete restoration of membrane dystrophin. These results demonstrate that IPC-mediated restoration of membrane dystrophin during reperfusion correlates with protection against contractile force-induced myocardial injury and suggest that the cardioprotection conferred by IPC can be enhanced by the temporary blockade of contractile activity until restoration of membrane dystrophin during reperfusion.
Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City 570-8507, Japan.
Masakuni
M
Kido
Hajime
H
Otani
Shiori
S
Kyoi
Tomohiko
T
Sumida
Hiroyoshi
H
Fujiwara
Takayuki
T
Okada
Hiroji
H
Imamura
D000818:Animals; D004396:Coloring Agents / Q000493:pharmacokinetics; D003931:Diacetyl / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016189:Dystrophin / Q000378:metabolism*; D005070:Evans Blue / Q000493:pharmacokinetics; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008566:Membranes / Q000378:metabolism; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D004396:Coloring Agents; D016189:Dystrophin; C004717:diacetylmonoxime; D005070:Evans Blue; D003931:Diacetyl