Objectives: The aim of this study was to examine whether selective plasminogen activator inhibitor type 1 (PAI-1) downregulation in the acutely ischemic heart increases the myocardial microvasculature and improves cardiomyocyte (CM) survival.
Background: Endogenous myocardial neovascularization is an important process enabling cardiac functional recovery after acute myocardial infarction. Expression of PAI-1, a potent inhibitor of angiogenesis, is induced in ischemic heart tissue.
Methods: A sequence-specific catalytic deoxyribonucleic acid (DNA) enzyme was used to reduce PAI-1 levels in cultured endothelial cells and in ischemic myocardium. At the time of coronary artery ligation, rats were randomized into three groups, each receiving an intramyocardial injection (IMI) of a single dose at three different sites of the peri-infarct region consisting, respectively, of DNA enzyme E2 targeting rat PAI-1 (E2), scrambled control DNA enzyme (E0), or saline. Cardiomyocyte apoptosis, capillary density, and echocardiography were studied two weeks following infarction.
Results: The E2 DNA enzyme, which efficiently inhibited rat PAI-1 expression in vitro, induced prolonged suppression (>2 weeks) of PAI-1 messenger ribonucleic acid and protein in rat heart tissues after a single IMI. At two weeks, hearts from experimental rats had over five-fold greater capillary density, 70% reduction in apoptotic CMs, and four-fold greater functional recovery compared with controls.
Conclusions: These results imply a causal relationship between elevated PAI-1 levels in ischemic hearts and adverse outcomes, and they suggest that strategies to reduce cardiac PAI-1 activity may augment neovascularization and improve functional recovery.
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