The Journal of Experimental Medicine
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Published online 13 December 2004 doi:10.1084/jem.20040221
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1657-1666
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Down-regulation of Plasminogen Activator Inhibitor 1 Expression Promotes Myocardial Neovascularization by Bone Marrow Progenitors

Guosheng Xiang, Michael D. Schuster, Tetsunori Seki, Alfred A. Kocher, Shawdee Eshghi, Andrew Boyle, and Silviu Itescu

Department of Surgery and Department of Medicine, Columbia University, New York, NY 10032

Address correspondence to Silviu Itescu, Columbia-Presbyterian Medical Center, 630 West 168th St., PH 14W, Room 1485, New York, NY 10032. Phone: (212) 305-7176; Fax: (212) 305-8304; email: si5{at}columbia.edu; or Guosheng Xiang, Columbia-Presbyterian Medical Center, 630 West 168th St., P&S 14-402, New York, NY 10032. Phone: (212) 305-1614; Fax: (212) 305-8145; email: gx15{at}columbia.edu

Human adult bone marrow–derived endothelial progenitors, or angioblasts, induce neovascularization of infarcted myocardium via mechanisms involving both cell surface urokinase-type plasminogen activator, and interactions between ß integrins and tissue vitronectin. Because each of these processes is regulated by plasminogen activator inhibitor (PAI)-1, we selectively down-regulated PAI-1 mRNA in the adult heart to examine the effects on postinfarct neovascularization and myocardial function. Sequence-specific catalytic DNA enzymes inhibited rat PAI-1 mRNA and protein expression in peri-infarct endothelium within 48 h of administration, and maintained down-regulation for at least 2 wk. PAI-1 inhibition enhanced vitronectin-dependent transendothelial migration of human bone marrow–derived CD34+ cells, and resulted in a striking augmentation of angioblast-dependent neovascularization. Development of large, thin-walled vessels at the peri-infarct region was accompanied by induction of proliferation and regeneration of endogenous cardiomyocytes and functional cardiac recovery. These results identify a causal relationship between elevated PAI-1 levels and poor outcome in patients with myocardial infarction through mechanisms that directly inhibit bone marrow–dependent neovascularization. Strategies that reduce myocardial PAI-1 expression appear capable of enhancing cardiac neovascularization, regeneration, and functional recovery after ischemic insult.

Key Words: myocardial infarction • angiogenesis • bone marrow stem cells • myocardial regeneration • DNA enzyme

Abbreviations used in this paper: HUVEC, human umbilical vein endothelial cell; LAD, left anterior descending; PAI, plasminogen activator inhibitor; u-PA, urokinase-type plasminogen activator.


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