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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

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