Apoptosis causes vascular cell injury and regulates vascular cell growth in response to injury. The investigators have described lung endothelial cell apoptosis caused by adenosine plus homocysteine (A/H). Their preliminary results indicate that A/H causes relocalization and caspase-induced degradation of selected components of focal adhesion (FA) complexes. FA complexes are tyrosine phosphorylated protein aggregates which mediate the interaction of extracellular matrix with cell cytoskeleton. Preliminary results indicate that protein tyrosine phosphatase (PTPase) activity is involved early in the mechanism of A/H-induced endothelial cell apoptosis. Protein tyrosine phosphorylation is important to maintenance of cytoskeletal organization and cell adhesion, and disruption of cell-substratum adhesion can cause apoptosis of anchorage-dependent cells. They propose that A/H activates PTP1B which, in turn, dephosphorylates focal adhesion (FA) kinase, allowing dissociation of DNA fragmentation and apoptosis. Using cultured bovine pulmonary artery endothelial cells (BPAEC) and the A/H model of apoptosis, they will determine: 1) whether A/H causes tyrosine dephosphorylation and dissociation of protein components of FA complexes; 2) whether PTPase activation is required for FA complex disruption; 3) whether over-expression of native FA kinase or a constitutively phosphorylated form of FA kinase blunts and whether over-expression of a dominant negative fragment of FA kinase enhances A/H-induced apoptosis and disruption of focal adhesion complexes; and 4) whether apoptosis is associated with relocalization and enhanced activation of PTP1B and whether over-expression of PTP1B enhances A/H apoptosis and disruption of FA complexes. These studies will provide important insights into the role of tyrosine phosphorylation of FA complexes in regulation of apoptosis. Understanding of endothelial apoptosis will allow development of means of regulating vascular injury and repair.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Lung Biology and Pathology Study Section (LBPA)
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Brown University
Internal Medicine/Medicine
Schools of Medicine
United States
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