Protection against oxidized low-density lipoprotein-induced vascular endothelial cell death by integrin-linked kinase.
BACKGROUND: Integrin-linked kinase (ILK) is a protein that plays important roles in extracellular matrix-mediated signaling. It has been shown that ILK is expressed preferentially in cardiac and skeletal muscles. Evidence points to its role as an upstream regulator of protein kinase B, a critical player in apoptosis. Because oxidized LDL (oxLDL) is thought to promote atherogenesis by causing the apoptosis of endothelial cells, we investigated the potential roles that ILK may play in oxLDL-induced apoptosis in vascular endothelial cells. METHODS AND RESULTS: Transcriptional and translational levels of ILK were investigated with reverse-transcriptase polymerase chain reaction and Western analysis. oxLDL treatment induced both the transcription and the translation of the ILK gene in endothelial cells. A recombinant adenovirus vector encoding the ILK gene was constructed to investigate its potential role in oxLDL-induced apoptosis in human umbilical vein endothelial cells and mouse lymphoid vein endothelial cells transformed by simian virus 40. In both types of cells, overexpression of the ILK gene significantly prevented oxLDL-induced apoptosis or cell death, as evaluated by 2 independent assay methods. Furthermore, we showed that ILK could inhibit oxLDL-induced upregulation of the kinase activity of p38 mitogen-activated protein kinase, which is often associated with stress-induced pro-apoptotic signal transduction. Finally, examination of other factors, such as bcl-2, bcl-xl, caspase 3, and caspase 9, demonstrated significant changes that were correlated with oxLDL treatment and ILK overexpression. CONCLUSIONS: ILK may be an important factor involved in the regulation of oxLDL-induced apoptosis in vascular endothelial cells. Modifying its activity may be a useful approach for prevention of endothelial cell injury in oxLDL-induced atherosclerosis.
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