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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064936-03
Application #
6530740
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Gail, Dorothy
Project Start
2000-04-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2002
Total Cost
$252,000
Indirect Cost
Name
Brown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Lu, Qing; Sakhatskyy, Pavlo; Newton, Julie et al. (2013) Sustained adenosine exposure causes lung endothelial apoptosis: a possible contributor to cigarette smoke-induced endothelial apoptosis and lung injury. Am J Physiol Lung Cell Mol Physiol 304:L361-70
Grinnell, Katie; Duong, Huetran; Newton, Julie et al. (2012) Heterogeneity in apoptotic responses of microvascular endothelial cells to oxidative stress. J Cell Physiol 227:1899-910
Lu, Qing; Rounds, Sharon (2012) Focal adhesion kinase and endothelial cell apoptosis. Microvasc Res 83:56-63
Lu, Qing; Newton, Julie; Hsiao, Vivian et al. (2012) Sustained adenosine exposure causes lung endothelial barrier dysfunction via nucleoside transporter-mediated signaling. Am J Respir Cell Mol Biol 47:604-13
Jankowich, Matthew D; Rounds, Sharon I S (2012) Combined pulmonary fibrosis and emphysema syndrome: a review. Chest 141:222-231
Casserly, Brian; Mazer, Jeffrey M; Vang, Alexander et al. (2011) C-type natriuretic peptide does not attenuate the development of pulmonary hypertension caused by hypoxia and VEGF receptor blockade. Life Sci 89:460-6
Lu, Qing; Sakhatskyy, Pavlo; Grinnell, Katie et al. (2011) Cigarette smoke causes lung vascular barrier dysfunction via oxidative stress-mediated inhibition of RhoA and focal adhesion kinase. Am J Physiol Lung Cell Mol Physiol 301:L847-57
Jankowich, Matthew D; Rounds, Sharon (2010) Combined pulmonary fibrosis and emphysema alters physiology but has similar mortality to pulmonary fibrosis without emphysema. Lung 188:365-73
Lu, Qing; Harrington, Elizabeth O; Newton, Julie et al. (2010) Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement. Am J Physiol Lung Cell Mol Physiol 298:L755-67

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