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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.

BACKGROUND AND PURPOSEResveratrol is a polyphenol abundantly found in grape skin and red wine. In the present study, we investigated whether resveratrol exerts protective effects against cardiac ischaemia/reperfusion and also explored its mechanisms. EXPERIMENTAL APPROACHInfarct size and functional recovery in rat isolated perfused hearts subjected to no-flow global ischaemia followed by reperfusion were measured. Cultured neonatal rat cardiomyocytes were exposed to H2O2 (100 mmol·L -1 ) to induce cell injury. Intracellular ion concentrations were measured using specific dyes. Western blotting was used to quantify protein expression levels. KEY RESULTSIn rat isolated perfused hearts, treatment with resveratrol (20 and 100 mmol·L -1 ) 15 min before ischaemia considerably improved left ventricular functional recovery and infarct size. In cultured neonatal rat cardiomyocytes, resveratrol significantly attenuated the increase in reactive oxygen species (ROS) and loss of mitochondrial inner membrane potential. Resveratrol also suppressed the increase in intracellular concentrations of Na + ([Na + ]i) and Ca 2+ ([Ca 2+ ]i) after H2O2 application; however, it did not suppress the ouabain-induced [Ca 2+ ]i increase. By measuring changes in intracellular pH recovery after acidification, we also confirmed that acid-induced activation of the Na + -H + exchanger (NHE) was prevented by pretreatment with resveratrol. Furthermore, resveratrol inhibited the H2O2-induced translocation of PKC-a from the cytosol to the cell membrane; this translocation is believed to activate NHE. CONCLUSION AND IMPLICATIONSResveratrol exerts cardioprotection by reducing ROS and preserving mitochondrial function. The PKC-a-dependent inhibition of NHE and subsequent attenuation of [Ca 2+ ]i overload may be a cardioprotective mechanism. AbbreviationsDYm, mitochondrial inner membrane potential; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LV, left ventricular; LVDP, left ventricular developed pressure; mitoKATP, mitochondrial ATP-sensitive K + channels; mPTP, mitochondrial permeability transition pore; NCX, Na + -Ca 2+ exchanger; NHE, Na + -H + exchanger; PI, propidium iodide; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; TMRE, tetramethylrhodamine ethyl ester

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp eperfusion therapy by primary percutaneous coronary intervention or thrombolysis is the most effective strategy to reduce mortality and improve the clinical outcome in acute myocardial infarction (AMI). However, reperfusion itself is associated with a risk of lethal ventricular arrhythmias. In fact, reperfusion-induced arrhythmias were identified in 30% of patients with successful reperfusion by thrombolysis. 1 Furthermore, in the majority of cases, successful restoration of coronary flow by primary angioplasty is accompanied by reperfusion-induced arrhythmias, including bradyarrhythmias, ventricular premature contractions (VPC), ventricular tachycardia (VT) and ventricular fibrillation (VF). 2 VT and VF by spontaneous recanalization are especially critical and underlie many cases of sudden cardiac death before hospital arrival. In a previous study of 12 patients who developed VF before the arrival of the ambulance, only one patient was discharged alive. 3 The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are attracting much attention because of their putative pleiotropic effects. We have reported that administration of atorvastatin in the early phase of an AMI improves cardiac function and attenuates B-type natriuretic peptide increase, and these effects were assumed to be independent of the drug's lipid-lowering effect. 4 Consistently, other reports have shown that early statin treatment for AMI patients decreases the risk of congestive heart failure and long-term mortality. 5,6 Several large clinical trials have also shown that statins reduce sudden cardiac death in patients with coronary