Down-regulation of Plasminogen Activator Inhibitor 1 Expression Promotes Myocardial Neovascularization by Bone Marrow Progenitors

Department of Surgery and Department of Medicine, Columbia University, New York, NY 10032
Journal of Experimental Medicine (Impact Factor: 12.52). 01/2005; 200(12):1657-66. DOI: 10.1084/jem.20040221
Source: PubMed


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 beta 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.

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Available from: Tetsunori Seki, Dec 23, 2013
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    • "Transcription of the PAI-1 gene is modulated by hypoxia [19]. Inhibition of PAI-1 using a PAI-1 selective antibody increased migration of human CD34+ across rat endothelial cell monolayer [20]. Moreover, the 4G/5G promoter allele of the PAI-1 gene is strongly linked to type 2 diabetes [21]. "
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