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. 2001 Jul 31;98(16):9336-41.
doi: 10.1073/pnas.171297498.

Gene program for cardiac cell survival induced by transient ischemia in conscious pigs

C Depre  1 , J E Tomlinson, R K Kudej, V Gaussin, E Thompson, S J Kim, D E Vatner, J N Topper, S F Vatner
Affiliations

Gene program for cardiac cell survival induced by transient ischemia in conscious pigs

C Depre et al. Proc Natl Acad Sci U S A. .

Abstract

Therapy for ischemic heart disease has been directed traditionally at limiting cell necrosis. We determined by genome profiling whether ischemic myocardium can trigger a genetic program promoting cardiac cell survival, which would be a novel and potentially equally important mechanism of salvage. Although cardiac genomics is usually performed in rodents, we used a swine model of ischemia/reperfusion followed by ventricular dysfunction (stunning), which more closely resembles clinical conditions. Gene expression profiles were compared by subtractive hybridization between ischemic and normal tissue of the same hearts. About one-third (23/74) of the nuclear-encoded genes that were up-regulated in ischemic myocardium participate in survival mechanisms (inhibition of apoptosis, cytoprotection, cell growth, and stimulation of translation). The specificity of this response was confirmed by Northern blot and quantitative PCR. Unexpectedly, this program also included genes not previously described in cardiomyocytes. Up-regulation of survival genes was more profound in subendocardium over subepicardium, reflecting that this response in stunned myocardium was proportional to the severity of the ischemic insult. Thus, in a swine model that recapitulates human heart disease, nonlethal ischemia activates a genomic program of cell survival that relates to the time course of myocardial stunning and differs transmurally in relation to ischemic stress, which induced the stunning. Understanding the genes up-regulated during myocardial stunning, including those not previously described in the heart, and developing strategies that activate this program may open new avenues for therapy in ischemic heart disease.

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Figures

Figure 1
Figure 1
Time course of functional recovery in stunned myocardium. A shows the anterior wall thickness in closed circles and the blood flow through the LAD artery (closed squares), as a percentage of baseline value (n = 5 in each group). B shows the measurement of blood flow by microspheres in subendocardium and subepicardium of ischemic myocardium at the end of the 90-min ischemia episode (reported as a percentage of baseline value). *, P < 0.05 versus baseline value.
Figure 2
Figure 2
Changes in gene expression analyzed by Northern blotting and in situ hybridization. (A) Northern blot was performed on samples of the remote and stunned area from five different hearts at 1-h reperfusion. Transcripts coding for PAI-1, PAI-2, and EGR-1 are illustrated. (B) Differences after 18S rRNA normalization between remote myocardium (open bars) and stunned myocardium (closed bars). *, P < 0.05 versus remote. (C) Tissue distribution by in situ hybridization. A clear induction was observed in cardiomyocytes from the ischemic area (stunned). (D) Changes in gene expression quantitated in isolated cardiomyocytes, prepared from the remote and stunned area of three different hearts submitted to 90-min ischemia and 1-h reperfusion. The graph illustrates the n-fold increase of PAI-1, PAI-2, and EGR-1 transcripts in stunned over normal myocytes.
Figure 3
Figure 3
Time course of changes in gene expression analyzed by qPCR. Transcripts were quantitatively measured in samples of the remote (open symbols) and stunned area (closed symbols) from hearts submitted to 90-min occlusion followed by no reperfusion or 1- or 12-h reperfusion (n = 5 in each group). The subendocardial (squares) and subepicardial areas (circles) were measured separately and compared with sham-operated animals (Sh). *, P < 0.05 versus corresponding value in remote myocardium. #, P < 0.05 versus corresponding value in subendocardium.
Figure 4
Figure 4
Action of the antiapoptotic genes detected in the subtracted library. The figure illustrates the two potential pathways of apoptosis activated by ischemia and the site of action of the different antiapoptotic products identified in the library.
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