Down-regulation of plasminogen activator inhibitor 1 expression promotes myocardial neovascularization by bone marrow progenitors.

Columbia-Presbyterian Medical Center, 630 West 168th St., PH 14W, Room 1485, New York, NY 10032, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 01/2005; 200(12):1657-66. DOI: 10.1084/jem.20040221
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we showed that transient inhibition of TGF- β1 resulted in correction of key aspects of diabetes-induced CD34(+) cell dysfunction. In this report, we examine the effect of transient inhibition of plasminogen activator inhibitor-1 (PAI-1), a major gene target of TGF-β1 activation. Using gene array studies, we examined CD34(+) cells isolated from a cohort of longstanding diabetic individuals, free of microvascular complications despite suboptimal glycemic control, and found that the cells exhibited reduced transcripts of both TGF-β1 and PAI-1 compared to age, sex, and degree of glycemic control-matched diabetic individuals with microvascular complications. CD34(+) cells from diabetic subjects with microvascular complications consistently exhibited higher PAI-1 mRNA than age-matched non-diabetic controls. TGF- β1 phosphorodiamidate morpholino oligo (PMO) reduced PAI-1 mRNA in diabetic (p<0.01) and non-diabetic (p=0.05) CD34(+) cells. To reduce PAI-1 in human CD34(+) cells, we utilized PAI-1 siRNA, lentivirus expressing PAI-1 shRNA or PAI-1 PMO. We found that inhibition of PAI-1 promoted CD34(+) cell proliferation and migration in vitro, likely through increased PI3(K) activity and increased cGMP production. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34(+) cells to injured acellular retinal capillaries was greater after PAI-1-PMO treatment compared with control PMO-treated cells. Targeting PAI-1 offers a promising therapeutic strategy for restoring vascular reparative function in defective diabetic progenitors.
    PLoS ONE 11/2013; 8(11):e79067. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity has assumed epidemic proportions and is expected to decrease the life expectancy of current and future generations by its cardiovascular complications and other associated chronic diseases. Recognizing the gravity of this trend, the American Heart Association recently identified obesity as an independent and important modifiable risk factor for cardiovascular disease. Obesity is known to cluster with other cardiovascular and metabolic risk factors constituting the cardiometabolic syndrome. The pathophysiogic link between obesity and cardiovascular disease is complex and involves multiple metabolic and inflammatory risk factors. In an attempt to better elucidate this major public health problem, this article reviews obesity as an epidemic, the structural and functional changes in the cardiovascular system as a result of obesity, and the pathophysiology of obesity-related cardiomyopathy. The sheer magnitude of the problem of obesity with its immense cardiovascular consequences warrants immediate intervention.
    Current Cardiovascular Risk Reports 03/2008; 2(2).
  • Archives of Biological Sciences 01/2013; 65(2):571-576. · 0.61 Impact Factor

Full-text (3 Sources)

Available from
May 23, 2014