Downregulated Expression of Plasminogen Activator Inhibitor-1 Augments Myocardial Neovascularization and Reduces Cardiomyocyte Apoptosis After Acute Myocardial Infarction
Guosheng Xiang, PhD*,
Michael D. Schuster, MS,
Tetsunori Seki, PhD,
Piotr Witkowski, MD,
Shawdee Eshghi, BS and
Silviu Itescu, MD
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.
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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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