Gene program for cardiac cell survival induced by transient ischemia in conscious pigs.
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.
Depre
C
C
Cardiovascular Research Institute, Department of Medicine, University of Medicine and Dentistry New Jersey, New Jersey Medical School, Newark, NJ 07103, USA. cdepre@humed.com
Tomlinson
J E
JE
Kudej
R K
RK
Gaussin
V
V
Thompson
E
E
Kim
S J
SJ
Vatner
D E
DE
Topper
J N
JN
Vatner
S F
SF
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000235:genetics*; D018076:DNA, Complementary; D005260:Female; D020869:Gene Expression Profiling; D017403:In Situ Hybridization; D017202:Myocardial Ischemia / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine
D018076:DNA, Complementary; D012333:RNA, Messenger