Objective: We sought to elucidate whether bone marrow cells ameliorate the outcomes of myocardial ischemia by reduction of cell death and to investigate whether the benefit is mediated by activation of intracellular kinases. Methods: Muscles from the right atrial appendage of patients were subjected to 90 minutes of normothermic simulated ischemia followed by 120 minutes of reoxygenation. Bone marrow cells from the same patients were co-incubated (10 5 cells per milligram of tissue) with the muscles during the entire experimental period. Some groups were treated with the protein kinase C inhibitor chelerythrine (10 μmol/L) or the p38 mitogen-activated protein kinase inhibitor SB203580 (10 μmol/L). Creatine kinase released into the media during the reoxygenation period was measured (international units per milligram of wet tissue), cell death by necrosis was assessed by propidium iodide, and cell death by apoptosis was assessed by deoxyuride-5′-triphosphate biotin nick end labeling (percentage of aerobic control values). Results: Creatine kinase release was significantly reduced (from 1.30 IU/mg wet tissue ± 0.11 to 0.33 IU/mg wet tissue ± 0.06; P < .05), and cell death by necrosis and apoptosis was abolished by bone marrow cells (from 30.1% ± 7.3% and 28.1% ± 3.9% to -5.6% ± 5.1% and 3.7% ± 5.0%, respectively; P < .05), an effect that was reversed by chelerythrine (13.4% ± 4.4% and 24.6% ± 8.2%, respectively) and by SB203580 (20.1% ± 2.4% and 19.5% ± 5.7%, respectively). Conclusions: Bone marrow cells have a potent effect against cell death of the human myocardium in the acute phase of ischemia that may explain, at least in part, the improvement in cardiac function and the reduction in infarct size seen when bone marrow cells are injected after a myocardial infarction. These findings may have important clinical implications to optimize cell therapy with bone marrow cells. In addition, the identification that the anti-ischemic effect of bone marrow cells is mediated by the kinases protein kinase C and p38 mitogen-activated protein kinase is also clinically relevant; it suggests that some of the beneficial effect of bone marrow cells can be obtained by the activation of intracellular signaling molecules, without the need for cell injection. © 2006 The American Association for Thoracic Surgery.
Kubal, C., Sheth, K., Nadal-Ginard, B., & Galiñanes, M. (2006). Bone marrow cells have a potent anti-ischemic effect against myocardial cell death in humans. Journal of Thoracic and Cardiovascular Surgery, 132(5), 1112–1118. https://doi.org/10.1016/j.jtcvs.2006.06.028