Down-regulation of plasminogen activator inhibitor 1 expression promotes myocardial neovascularization by bone marrow progenitors.
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.
Xiang
Guosheng
G
Columbia-Presbyterian Medical Center, 630 West 168th St., PH 14W, Room 1485, New York, NY 10032, USA.
Schuster
Michael D
MD
Seki
Tetsunori
T
Kocher
Alfred A
AA
Eshghi
Shawdee
S
Boyle
Andrew
A
Itescu
Silviu
S
D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000235:genetics; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D006321:Heart / Q000502:physiology*; D006801:Humans; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012038:Regeneration / Q000235:genetics / Q000502:physiology*
D018952:Antigens, CD34; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D004247:DNA