Role of extracellular signal-regulated kinase for endothelial progenitor cell dysfunction in coronary artery disease

• Published in: Basic research in cardiology Vol. 104; no. 5; pp. 613 - 620
• Main Authors: Friedrich, Erik B., Werner, Christian, Walenta, Katrin, Böhm, Michael, Scheller, Bruno
• Format: Journal Article
• Language: English
• Published: Heidelberg D. Steinkopff-Verlag 01.09.2009; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Cardiology; Case-Control Studies; Cell Adhesion - drug effects; Cells, Cultured; Chemokine CXCL12 - metabolism; Coronary Artery Disease - enzymology; Coronary Artery Disease - pathology; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelial Cells - pathology; Female; Humans; Male; MAP Kinase Kinase 2 - genetics; MAP Kinase Kinase 2 - metabolism; Medicine; Medicine & Public Health; Middle Aged; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Mutation; Original Contribution; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Signal Transduction - drug effects; Stem Cells - drug effects; Stem Cells - enzymology; Stem Cells - pathology; Time Factors; Transfection; Extracellular signal-regulated kinase; Stromal-derived factor-1; Adhesion; Coronary artery disease; Endothelial progenitor cells
• ISSN: 0300-8428; 1435-1803; 1435-1803
• DOI: 10.1007/s00395-009-0022-6

In patients with coronary artery disease (CAD), number and function of endothelial progenitor cells (EPCs) are down-regulated. The relevant intracellular signalling mechanisms responsible for dysfunction of EPCs in CAD remain poorly characterized. Our goal was to examine the regulation of ERK-1/2 by SDF-1 and the role of ERK-1/2 for adhesion in EPCs. Western analysis revealed that the chemokine SDF-1 (SDF-1, 100 nM) mediates phosphorylation of ERK-2 after 90 s with a maximum after 180–300 s in EPCs isolated from healthy control subjects, while EPCs from patients with CAD are characterized by a temporally delayed and quantitatively markedly attenuated SDF-1-triggered ERK-2-phosphorylation. Functionally, EPCs isolated from patients with CAD display reduced SDF-1-induced adhesion under flow conditions, while augmenting ERK-2 signalling using an activating MEK-2 cDNA construct restores adhesion to control levels and rescues the adhesion defect of CAD-EPCs. These data indicate that defects in SDF-1-triggered EPC-adhesion contribute to the functional impairment of EPCs in CAD, and that ERK-2 represents a new therapeutic target for functional improvement of EPC adhesion in CAD.