Effects of plasminogen activator inhibitor-1-specific RNA Aptamers on cell adhesion, motility, and tube formation

Stephanie Brandal, Charlene M. Blake, Bruce A. Sullenger, Yolanda M Fortenberry

Research output: Contribution to journalArticle

Abstract

The serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is associated with the pathophysiology of several diseases, including cancer and cardiovascular disease. The extracellular matrix protein vitronectin increases at sites of vessel injury and is also present in fibrin clots. Integrins present on the cell surface bind to vitronectin and anchor the cell to the extracellular matrix. However, the binding of PAI-1 to vitronectin prevents this interaction, thereby decreasing both cell adhesion and migration. We previously developed PAI-1-specific RNA aptamers that bind to (or in the vicinity of) the vitronectin binding site of PAI-1. These aptamers prevented cancer cells from detaching from vitronectin in the presence of PAI-1, resulting in an increase in cell adhesion. In the current study, we used in vitro assays to investigate the effects that these aptamers have on human aortic smooth muscle cell (HASMC) and human umbilical vein endothelial cell (HUVEC) migration, adhesion, and proliferation. The PAI-1-specific aptamers (SM20 and WT15) increased attachment of HASMCs and HUVECs to vitronectin in the presence of PAI-1 in a dose-dependent manner. Whereas PAI-1 significantly inhibited cell migration through its interaction with vitronectin, both SM20 and WT15 restored cell migration. The PAI-1 vitronectin binding mutant (PAI-1AK) did not facilitate cell detachment or have an effect on cell migration. The effect on cell proliferation was minimal. Additionally, both SM20 and WT15 promoted tube formation on matrigel that was supplemented with vitronectin, thereby reversing the PAI-1′s inhibition of tube formation. Collectively, results from this study show that SM20 and WT15 bind to the PAI-1′s vitronectin binding site and interfere with its effect on cell migration, adhesion, and tube formation. By promoting smooth muscle and endothelial cell migration, these aptamers can potentially eliminate the adverse effects of elevated PAI-1 levels in the pathogenesis of vascular disease.

Original languageEnglish (US)
Pages (from-to)373-381
Number of pages9
JournalNucleic Acid Therapeutics
Volume21
Issue number6
DOIs
StatePublished - Dec 1 2011

Fingerprint

Nucleotide Aptamers
Vitronectin
Plasminogen Activator Inhibitor 1
Cell adhesion
Cell Adhesion
Cell Movement
Polyamideimides
Endothelial cells
Smooth Muscle Myocytes
Muscle
Adhesion
Binding Sites
Cells
Cell Proliferation
Serine Proteinase Inhibitors
Extracellular Matrix Proteins
Human Umbilical Vein Endothelial Cells
Cell proliferation
Fibrin
Anchors

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Biochemistry
  • Drug Discovery

Cite this

Effects of plasminogen activator inhibitor-1-specific RNA Aptamers on cell adhesion, motility, and tube formation. / Brandal, Stephanie; Blake, Charlene M.; Sullenger, Bruce A.; Fortenberry, Yolanda M.

In: Nucleic Acid Therapeutics, Vol. 21, No. 6, 01.12.2011, p. 373-381.

Research output: Contribution to journalArticle

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