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Mitochondrial KATP channels-derived reactive oxygen species activate pro-survival pathway in pravastatin-induced cardioprotection

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Abstract

Reactive oxygen species (ROS) are important intracellular signaling molecules and are implicated in cardioprotective pathways including ischemic preconditioning. Statins have been shown to have cardioprotective effects against ischemia/reperfusion injury, however, the precise mechanisms remain to be elucidated. We hypothesized that ROS-mediated signaling cascade may be involved in pravastatin-induced cardioprotection. Cultured rat cardiomyocytes were exposed to H2O2 for 30 min to induce cell injury. Pravastatin significantly suppressed H2O2-induced cell death evaluated by propidium iodide staining and the MTT assay. Incubation with pravastatin activated catalase, and prevented a ROS burst induced by H2O2, which preserved mitochondrial membrane potential. Protective effects were induced very rapidly within 10 min, which was concordant with the up-regulation of phosphorylated ERK1/2. L-NAME, 5HD, N-acetylcysteine (NAC) and staurosporine inhibited ERK1/2 phosphorylation and also reduced pravastatin-induced cardioprotection, suggesting NO, mitochondrial KATP (mitoKATP) channels, ROS and PKC should be involved in the cardioprotective signaling. We also demonstrated that pravastatin moderately up-regulated ROS generation in a 5HD-inhibitable manner. In isolated perfused rat heart experiments, pravastatin administered 10 min prior to no-flow global ischemia significantly improved left ventricular functional recovery, and also reduced infarct size, which were attenuated by the treatment with NAC, 5HD, L-NAME or staurosporine. Administration of pravastatin from the beginning of reperfusion also conferred cardioprotection. Pravastatin protected the cardiomyocytes against oxidative stress by preventing the ROS burst and preserving mitochondrial function. Moderately up-regulated ROS production by mitoKATP channels opening is involved in the pro-survival signaling cascade activated by pravastatin.

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Authors and Affiliations

  1. Department of Laboratory Examination and Diagnostics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Yufu-city, Oita, 879-5593, Japan

    Luong Cong Thuc, Yasushi Teshima, Naohiko Takahashi, Yasuko Nagano-Torigoe, Kaori Ezaki, Kunio Yufu, Mikiko Nakagawa & Tetsunori Saikawa

  2. Department of Internal Medicine I, Faculty of Medicine, Oita University, Oita, Japan

    Masahide Hara

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  1. Luong Cong Thuc
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  2. Yasushi Teshima
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Correspondence to Yasushi Teshima.

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Thuc, L.C., Teshima, Y., Takahashi, N. et al. Mitochondrial KATP channels-derived reactive oxygen species activate pro-survival pathway in pravastatin-induced cardioprotection. Apoptosis 15, 669–678 (2010). https://doi.org/10.1007/s10495-010-0473-0

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