Molecular dynamics of the compensatory response to myocardial infarct.
Myocardial infarct via occlusion of the left anterior descending coronary in rats caused overriding depression in transcription, signal transduction, inflammation and extracellular matrix pathways in the infarct zone within 24 h. In contrast, remote zone gene expression was reciprocally activated during the immediate post-infarct period. Infarct zone signal transduction occurred primarily through TGFbeta1 induction while the remote zone exhibited elevated WNT, NOTCH, GPCR and transmembrane signaling. A minimal day 1 acute phase, inflammatory response was detected in the infarct zone while interleukins (IL1alpha, IL1beta, IL6, IL12alpha, IL18) and the TNFalpha superfamily were activated in the remote zone. Different cytochrome subsets were activated in each left ventricular region on day 1 while anti-oxidant genes were elevated only in the remote zone. The infarct zone exhibited mixed early transcription factor activation across all binding domains with a balance favoring constitutive gene activation and differentiation pathways as opposed to cell proliferation. In contrast, the remote zone exhibited activation of extensive developmental transcription factors involved in specification of cell phenotype, tissue-specific interactions and position-specific cell proliferation on day 1. The day 28 infarct zone response mirrored the day 1 remote zone response including activation of genes associated with matrix remodeling (metallothionein and metalloproteinase 9, 12, 23), as well as genes associated with cell proliferation and phenotype specification (MYC, EGR2, ATF3, HOXA1) recapitulating developmental histogenesis programs.
LaFramboise
W A
WA
Department of Cardiothoracic Surgery, Allegheny General Hospital, Drexel University School of Medicine, 320 East North Avenue, Pittsburgh, PA 15212, USA. laframboisewa@upmc.edu
Bombach
K L
KL
Dhir
R J
RJ
Muha
N
N
Cullen
R F
RF
Pogozelski
A R
AR
Turk
D
D
George
J D
JD
Guthrie
R D
RD
Magovern
J A
JA
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D007249:Inflammation / Q000235:genetics; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation
D012333:RNA, Messenger; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System