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1 Department of Medicine, University of Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: p-schumacker{at}northwestern.edu.
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 non-receptor 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'-dihydrodichlorofluorescein (DCFH), increased 152±16% during 1.5 hr of cyclic strain relative to unstrained controls. The mitochondrial inhibitors DPI (5 µM) or rotenone (2 µM) attenuated this increase, whereas L-nitroarginine (L-NA; 100µM), allopurinol (100µM), or apocynin (30µM) had no effect. The antioxidants ebselen (5µM) and DDC (1mM) inhibited the strain-induced increase in oxidant signaling, but Hb (5µM) had no effect. These results indicate that strain induces oxidant release from mitochondria. Treatment with cytochalasin D (5µM) 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 Go-6976. These findings indicate that mitochondrial oxidants generated in response to endothelial strain trigger FAK phosphorylation through a signaling pathway that involves PKC.
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