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Downregulated Expression of Plasminogen Activator Inhibitor-1 Augments Myocardial Neovascularization and Reduces Cardiomyocyte Apoptosis After Acute Myocardial Infarction

Departments of Surgery and Medicine, Columbia University, New York, New York

Manuscript received February 1, 2005; revised manuscript received March 30, 2005, accepted April 13, 2005.

^_* Reprint requests and correspondence: Dr. Guosheng Xiang, Columbia-Presbyterian Medical Center, 630 West 168th Street, P&S 14-402, New York, New York 10032 (Email: gx15{at}columbia.edu).

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.

Abbreviations and Acronyms   AMI = acute myocardial infarction   CM = cardiomyocyte   DNA = deoxyribonucleic acid   EC = endothelial cell   E0 = scrambled control deoxyribonucleic acid enzyme E0   E2 = deoxyribonucleic acid enzyme E2 targeting rat plasminogen activator inhibitor type 1   IHC = immunohistochemical staining   IMI = intramyocardial injection   LAD = left anterior descending coronary artery   mRNA = messenger ribonucleic acid   PIR = peri-infarct region   PAI-1 = plasminogen activator inhibitor type 1

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