Abstract
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-1alpha, 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Animals
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Apoptosis / genetics
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Cell Survival / genetics
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Female
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Gene Expression Profiling
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Gene Expression Regulation*
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Glucose Transporter Type 1
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HSP70 Heat-Shock Proteins / biosynthesis
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HSP70 Heat-Shock Proteins / genetics
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Heat-Shock Proteins
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Inhibitor of Apoptosis Proteins
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Magnetic Resonance Imaging, Cine
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Male
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Middle Aged
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Models, Animal
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Molecular Chaperones
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Monosaccharide Transport Proteins / biosynthesis
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Monosaccharide Transport Proteins / genetics
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Myocardial Ischemia / genetics
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Myocardial Stunning / diagnostic imaging
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Myocardial Stunning / genetics*
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / metabolism*
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Positron-Emission Tomography
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Proteins / genetics
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Proteins / metabolism
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RNA, Messenger / biosynthesis
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Sus scrofa
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / genetics
Substances
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DNA-Binding Proteins
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Glucose Transporter Type 1
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HIF1A protein, human
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HSP70 Heat-Shock Proteins
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HSPB8 protein, human
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Heat-Shock Proteins
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Inhibitor of Apoptosis Proteins
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Molecular Chaperones
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Monosaccharide Transport Proteins
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Nuclear Proteins
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Proteins
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RNA, Messenger
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SLC2A1 protein, human
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Protein Serine-Threonine Kinases