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Cardioprotective effects of the novel Na+/H+ exchanger-1 inhibitor KR-32560 in a perfused rat heart model of global ischemia and reperfusion: Involvement of the Akt-GSK-3β cell survival pathway and antioxidant enzyme

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Abstract

To investigate the cardioprotective effects and mechanism of action of KR-32560 {[5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine}, a newly synthesized NHE-1 inhibitor, we evaluated the effects of KR-32560 on cardiac function in a rat model of ischemia/reperfusion (I/R)-induced heart injury as well as the role antioxidant enzymes and pro-survival proteins play these observed effects. In isolated rat hearts subjected to 25 min of global ischemia followed by 30 min of reperfusion, KR-32560 (3 and 10 μM) significantly reversed the I/Rinduced decrease in left ventricular developed pressure and increase in left ventricular enddiastolic pressure. In rat hearts reperfused for 30 min, KR-32560 (10 μM) significantly decreased the malondialdehyde content while increasing the activities of both glutathione peroxidase and catalase, two important antioxidant enzymes. Western blotting analysis of left ventricles subjected to I/R showed that KR-32560 significantly increased phosphorylation of both Akt and GSK-3β in a dose-dependent manner, with no effect on the phosphorylation of eNOS. These results suggest that KR-32560 exerts potent cardioprotective effects against I/Rinduced rat heart injury and that its mechanism involves antioxidant enzymes and the Akt-GSK-3β cell survival pathway.

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Authors and Affiliations

  1. Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University, Chungju, 380-701, Korea

    In-Sang Jung, Sung-Hun Lee, Min-Kyu Yang, Jung-Woo Park & Hwa-Sup Shin

  2. Medical Science Division, Korea Research Institute of Chemical Technology, Taejeon, 305-343, Korea

    Kyu-Yang Yi & Sung-Eun Yoo

  3. Rexgene Biotech Co. Ltd, Seoul, 137-070, Korea

    Suk-Hyung Kwon

  4. College of Medicine, Konkuk University, Chungju, 380-701, Korea

    Hun-Jong Chung & Wahn-Soo Choi

  5. Department of Applied Biochemistry, College of Biomedical and Health Science, Konkuk University, Chungju, 380-701, Korea

    Hwa-Sup Shin

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  1. In-Sang Jung
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Jung, IS., Lee, SH., Yang, MK. et al. Cardioprotective effects of the novel Na+/H+ exchanger-1 inhibitor KR-32560 in a perfused rat heart model of global ischemia and reperfusion: Involvement of the Akt-GSK-3β cell survival pathway and antioxidant enzyme. Arch. Pharm. Res. 33, 1241–1251 (2010). https://doi.org/10.1007/s12272-010-0815-z

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