P568Mechanisms involved in cardioprotective effects of statins administered during reoxygenation in human myocardium, in vitro

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Abstract

Purpose

Reperfusion is a double-edged sword and can itself induce severe and also irreversible damage to the myocardium: the reperfusion injury. New therapeutic approach will need to be focused on limiting reperfusion-induced injury following an acute myocardial infarction resulting in increased salvage of ischemic myocardium, and subsequently improved mortality and morbidity. Statins have been reported to have pleiotropic effects on the cardiovascular system, beyond their ability to lower cholesterol. This present work investigated the effect of pravastatin when administered at the point of reoxygenation following severe hypoxia using human atrial muscle taken from patients undergoing coronary artery bypass surgery and aortic valve replacement. Then, we have examined the involvement of nitric oxyde synthase, mitochondrial Permeability Transition Pore (mPTP), and expression of markers of apoptosis in human myocardium, in vitro.

Methods

After the approval of local medical ethics committee, human right atrial appendages were obtained during cannulation for cardiopulmonary bypass. The force of contraction (34°C, stimulation frequency 1Hz) of right atrial trabeculae was recorded during 30-min hypoxia followed by 60-min reoxygenation (control group). In statins groups, after a 30-min hypoxic period, pravastatin (5µM, 10µM, 50µM, 75µM) was administered during the time of reoxygenation. In separate groups, pravastatin 50µM was administered in presence of L-NAME 200µM, a nitric oxyde synthase inhibitor and atractyloside 50µM, the mPTP opener. The primary endpoint was the developed force of contraction at the end of reoxygentation, expressed as a percentage of baseline. Protein expression of BAD, phospho-BAD, caspase 3, Pim-1 kinase and Bcl-2 were measured using Western immunoblotting.

Results

Pravastatin 10µM (77 ± 5% of baseline), 50µM (86 ± 6%) and 75µM (88 ± 13%) improved the force of contraction at the end of reoxygenation, as compared with Control group (49 ± 11%; P < 0.001). These beneficial effects were prevented by L-NAME and atractyloside. As compared to control group pravastatin 5µM did not modify the force of contraction. Pravastatin increased the phosphorylation of BAD, activated the expression of Pim-1 kinase and Bcl-2, and maintained the caspase 3 level, relative to their respective untreated controls.

Conclusions

Pravastatin, administered at reoxygenation, protect the human myocardium against hypoxia-reoxygenation injuries by preventing the mPTP opening, phosphorylating BAD, activating nitric oxyde synthase, Pim-1 kinase, Bcl-2 and preserving the myocardium against the caspase 3 activation.

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