Published online before print July 8, 2004, doi: 10.1161/01.RES.0000138301.42713.18
© 2004 American Heart Association, Inc.
Integrative Physiology |
Program of Cell Survival Underlying Human and Experimental Hibernating Myocardium
From the Department of Cell Biology and Molecular Medicine and the Cardiovascular Research Institute (C.D., S.-J.K., Y.H., V.G., D.E.V., S.F.V.), University of Medicine and Dentistry New Jersey, Newark; National Heart and Lung Institute (A.S.J., O.E.R., J.R.P., G.D.D., D.J.P., P.G.C.), Imperial College, London, UK; and Medical Research Council Clinical Sciences Centre (O.E.R., P.G.C.), London, UK.
Correspondence to Stephen F. Vatner, MD, Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Ave, MSB G-609, Newark, NJ 07103. E-mail vatnersf{at}umdnj.edu
Hibernating myocardium refers to chronically dysfunctional myocardium in patients with coronary artery disease in which cardiac viability is maintained and whose function improves after coronary revascularization. It is our hypothesis that long-term adaptive genomic mechanisms subtend the survival capacity of this ischemic myocardium. Therefore, the goal of this study was to determine whether chronic repetitive ischemia elicits a gene program of survival protecting hibernating myocardium against cell death. Accordingly, we measured the expression of survival genes in hibernating myocardium, both in patients surgically treated for hibernation and in a chronic swine model of repetitive ischemia reproducing the features of hibernation. Human hibernating myocardium was characterized by an upregulation of genes and corresponding proteins involved in anti-apoptosis (IAP), growth (VEGF, H11 kinase), and cytoprotection (HSP70, HIF-1
, GLUT1). In the swine model, the same genes and proteins were upregulated after repetitive ischemia, which was accompanied by a concomitant decrease in myocyte apoptosis. These changes characterize viable tissue, because they were not found in irreversibly injured myocardium. Our report demonstrates a novel mechanism by which the activation of an endogenous gene program of cell survival underlies the sustained viability of the hibernating heart. Potentially, promoting such a program offers a novel opportunity to salvage postmitotic tissues in conditions of ischemia.
Key Words: gene expression • coronary artery disease • ischemia • stunning • hibernation
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