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

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 H(2)O(2) for 30 min to induce cell injury. Pravastatin significantly suppressed H(2)O(2)-induced cell death evaluated by propidium iodide staining and the MTT assay. Incubation with pravastatin activated catalase, and prevented a ROS burst induced by H(2)O(2), 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 K(ATP) (mitoK(ATP)) 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 mitoK(ATP) channels opening is involved in the pro-survival signaling cascade activated by pravastatin.

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

“…Using isolated cardiac cells, we also reported that the protection observed is primarily due to a direct effect on the cardiomyocytes and does not necessarily depend on the endothelial effects of CST [36]. Since in multiple models [39,41,42,51,52,56], including isolated cells [48,51,56], an involvement of PI3K/Akt, PKCs, mitoK ATP channel and ROS-signalling have been observed in ischaemic postconditioning, we hypothesized that the CST-induced cardioprotective response in reperfusion may involve potential signalling proteins (e.g. PI3K/Akt and PKCs) and potential downstream targets and mediators (e.g.…”

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

“…The effects of statins on cardiac mitochondria are unclear. Pravastatin was shown to mediate cardioprotection through mitochondrial ATP-sensitive potassium (mitoK ATP ) channels in a Langendorff model where the drug was infused 10 min before global no-flow ischemia (55). Opening of mitoK ATP channels is known to cause mild mitochondrial depolarization; we previously showed that depolarization mediated by the uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) was sufficient to trigger Parkin translocation and mitophagy (18).…”

Is immunity a mechanism contributing to statin-induced diabetes?

“…Increased production of mitochondrial reactive oxygen species (mtROS), altered mitochondrial membrane potential and decreased intracellular ATP levels have been observed with concentrations of statin as low as 1 mM. [68][69][70][71][72] Statins have also been shown to promote a modest increase in cellular ROS and an increase of ATP release in THP-1 monocytes. 56 Statininduced IL-1b production was also shown to be dependent on P2X purinoceptor 7 (P2X7) activation.…”