What is the clinical evidence from this study?

Study design: Other. Population: Streptozotocin-induced diabetes and ischemia/reperfusion injury (n=50). Intervention: Chelerythrine or staurosporine (PKC inhibitors) vs. Absence of PKC inhibitors. Primary outcome: Cardioprotection (time to onset of contracture, recovery of LV function, incidence of VT/VF, released CK).

January 1, 2003Open Access

Ischemia-Induced Translocation of Protein Kinase C-.EPSILON. Mediates Cardioprotection in the Streptozotocin-Induced Diabetic Rat

TOTatsuhiko OoieOtsuka (Japan)NTNaohiko TakahashiElectrophysiology TNTomoko NawataOita University

Key Result

In isolated perfused hearts from STZ-induced diabetic rats, cardioprotection against ischemia/reperfusion injury was abolished by PKC inhibitors, indicating that persistent translocation of PKC-ε mediates this protective effect.

Structured PICO

Does persistent translocation of PKC-epsilon mediate cardioprotection against ischemia/reperfusion injury in STZ-induced diabetic rats?

Population

50 male Wistar-King rats, 12 weeks after streptozotocin-induced diabetes or vehicle injection, subjected to isolated heart perfusion and ischemia/reperfusion.

Intervention

30 minutes of global ischemia followed by 30 minutes of reperfusion in the presence or absence of 50 nmol/L staurosporine or 2 mumol/L chelerythrine using a Langendorff apparatus

Comparator

Control (vehicle-injected) rat hearts

Outcome

Translocation of PKC-alpha, -beta, -delta and -epsilon isoforms, time to onset of contracture, recovery of left ventricular function, incidence of VT/VF, and amount of released creatine kinase (CK)surrogate

Persistent translocation of PKC-epsilon during ischemia mediates cardioprotection against ischemia/reperfusion injury in STZ-induced diabetic rats.

Limitations

The use of 5 min of low-flow ischemia preceding a 25-min no-flow ischemia complicates the interpretation of results because the effects of low-flow ischemia on myocardial injury are distinct from those of no-flow ischemia.
Cardiac function at baseline was significantly lower in the diabetic hearts than in the control hearts, which may contribute to the tolerance of ischemic insult because the diabetic hearts may require less energy.

Abstract

The present study investigated the role of translocation of protein kinase C (PKC) during ischemia/reperfusion in cardioprotection in the streptozotocin (STZ)-induced diabetic rat. Twelve weeks after injection of STZ or vehicle, male Wister-King rat hearts were isolated and perfused in the presence or absence of 50 nmol/L staurosporine or 2 mumol/L chelerythrine using a Langendorff apparatus. Thirty minutes of global ischemia was followed by the same period of reperfusion. The time to onset of contracture was determined during ischemia. The recovery of left ventricular function, incidence of ventricular tachycardia/fibrillation (VT/VF), and amount of released creatine kinase (CK) were determined during the reperfusion period. Translocation of the PKC-alpha, -beta, -delta and -epsilon isoforms was determined by immunoblotting. Development of contracture was delayed, the recovery of left ventricular function was greater, and the incidence of VT/VF and amount of released CK were lower in diabetic than in control hearts. Ischemia caused an increase in the particulate/cytosolic fraction ratio of the PKC- epsilon isoform in the diabetic and control hearts. However, this translocation of PKC-epsilon during ischemia was transient in the control heart, but was persistent in the diabetic heart. The ischemia-induced translocation of PKC-epsilon was abolished by chelerythrine perfusion. These results suggest that persistent translocation of PKC-epsilon during ischemia plays a major role in cardioprotection against ischemia/reperfusion injury in STZ-induced diabetic rats.

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