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This Article Full Text Full Text (PDF) All Versions of this Article: 291/1/L38    most recent 00287.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Ali, M. H. Articles by Schumacker, P. T. Search for Related Content PubMed PubMed Citation Articles by Ali, M. H. Articles by Schumacker, P. T.

Stretch-induced phosphorylation of focal adhesion kinase in endothelial cells: role of mitochondrial oxidants

Department of Medicine, Section of Pulmonary and Critical Care, The University of Chicago, Chicago, Illinois

Submitted 27 July 2004 ; accepted in final form 13 January 2006

Mechanical stretch activates a number of signaling pathways in endothelial cells, and it elicits a variety of functional responses including increases in the phosphorylation of focal adhesion kinase (FAK), a nonreceptor tyrosine kinase involved in integrin-mediated signal transduction. Stretch also triggers an increase in the generation of reactive oxygen species (ROS), which may function as second messengers in the signal transduction cascades that activate cellular responses to strain. Mitochondria represent an important source of ROS in the cell, and these organelles may release ROS in response to strain by virtue of their attachment to cytoskeletal proteins. We therefore tested whether cyclic stretch increases FAK phosphorylation at Tyr397 through a mitochondrial ROS signaling pathway in bovine pulmonary artery endothelial cells (BPAEC). Oxidant signaling, measured using 2'7'-dichlorofluorescin (DCFH), increased 152 ± 16% during 1.5 h of cyclic strain relative to unstrained controls. The mitochondrial inhibitors diphenylene iodonium (5 µM) or rotenone (2 µM) attenuated this increase, whereas L-nitroarginine (100 µM), allopurinol (100 µM), or apocynin (30 µM) had no effect. The antioxidants ebselen (5 µM) and dithiodidiethyldithiocarbamate (1 mM) inhibited the strain-induced increase in oxidant signaling, but Hb (5 µM) had no effect. These results indicate that strain induces oxidant release from mitochondria. Treatment with cytochalasin D (5 µM) abrogated strain-induced DCFH oxidation in BPAEC, indicating that actin filaments were required for stretch-induced mitochondrial ROS generation. Cyclic strain increased FAK phosphorylation at Tyr397, but this was abolished by mitochondrial inhibitors as well as by antioxidants. Strain-induced FAK phosphorylation was abrogated by inhibition of protein kinase C (PKC) with Ro-31-8220 or Gö-6976. These findings indicate that mitochondrial oxidants generated in response to endothelial strain trigger FAK phosphorylation through a signaling pathway that involves PKC.

reactive oxygen species; superoxide; cytoskeleton; cyclic stretch; protein kinase C

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