Mechanisms Involved in Cardioprotective Effects of Pravastatin Administered during Reoxygenation in Human Myocardium In Vitro

Sandrine Lemoine, Stéphane Allouche, Laurent Coulbault, Valérie Cornet, Massimo Massetti, Philippe Galera, Jean-Louis Gérard, Jean-Luc Hanouz
2012 Anesthesiology  
The authors investigated the effect of pravastatin during reoxygenation after myocardial hypoxia and examined the involvement of nitric oxide synthase, mitochondrial permeability transition pore, and expression of markers of apoptosis in human myocardium in vitro. Methods: Human atrial trabeculae were exposed to hypoxia for 30 min and reoxygenation for 60 min (control group; n ϭ 10). Pravastatin (5, 10, 50, 75 M; n ϭ 6 in each group) was administered throughout the reoxygenation. In separate
more » ... ups (n ϭ 6 in each group), pravastatin 50 M was administered in the presence of 200 M L-NG-nitroarginine methyl ester, a nitric oxide synthase inhibitor, and 50 M atractyloside, the mitochondrial permeability transition pore opener. The primary endpoint was the developed force of contraction at the end of reoxygenation, expressed as a percentage of baseline (mean Ϯ SD). Protein expression of BAD, phospho-BAD, caspase 3, Pim-1 kinase, and Bcl-2 were measured using Western immunoblotting. Results: The administration of 10 (77 Ϯ 5% of baseline), 50 (86 Ϯ 6%), and 75 M (88 Ϯ 13%) pravastatin improved the force of contraction at the end of reoxygenation, compared with that of the control group (49 Ϯ 11%; P Ͻ 0.001). These beneficial effects were prevented by L-NG-nitroarginine methyl ester and atractyloside. Compared with control group, the administration of 5 M pravastatin 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 concentration relative to that of the respective untreated controls. Conclusions: Pravastatin, administered at reoxygenation, protected the human myocardium by preventing the mitochondrial permeability transition pore opening, phosphorylating BAD, activating nitric oxide synthase, Pim-1 kinase, and Bcl-2, and preserving the myocardium against the caspase 3 activation. P ERIOPERATIVE myocardial ischemia is a major adverse event that dramatically increases postoperative morbidity and mortality. The restoration of oxygenated
doi:10.1097/aln.0b013e31824be77c pmid:22343498 fatcat:riwrbnsr7fbd7nh5yyy7gtj3ee