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(Circulation. 2000;101:797.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Anti-Ischemic Effect of a Novel Cardioprotective Agent, JTV519, Is Mediated Through Specific Activation of -Isoform of Protein Kinase C in Rat Ventricular Myocardium

Koichi Inagaki, MD; Yasuki Kihara, MD, PhD; Wataru Hayashida, MD, PhD; Toshiaki Izumi, MD; Yoshitaka Iwanaga, MD, PhD; Takeshi Yoneda, MD; Yuzo Takeuchi, MD; Katsuo Suyama, MD; Eri Muso, MD, PhD; Shigetake Sasayama, MD, PhD

From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Correspondence to Yasuki Kihara, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin, Sakyo, Kyoto 606-8507, Japan. E-mail kihara{at}kuhp.kyoto-u.ac.jp

Background—A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca²⁺ overload–induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts.

Methods and Results—At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by ₁-, A₁-, and B₂-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the -isoform but not the other isoforms of PKC to the plasma membrane.

Conclusions—The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.

Key Words: ischemia • JTV519 • reperfusion • pharmacology • immunohistochemistry

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