Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 200, Issue 12, Pages 1657-1666Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20040221
Keywords
myocardial infarction; angiogenesis; bone marrow stem cells; myocardial regeneration; DNA enzyme
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Funding
- NHLBI NIH HHS [RFA-HL-02-017] Funding Source: Medline
- NIA NIH HHS [RFA-AG-01-006] Funding Source: Medline
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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 expression appear capable of enhancing cardiac neovascularization, regeneration, and functional recovery after ischemic insult.
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