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(Circulation Research. 2007;101:97.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Flow Antagonizes TNF- Signaling in Endothelial Cells by Inhibiting Caspase-Dependent PKC Processing

Gwenaele Garin, Jun-ichi Abe, Amy Mohan, Weimin Lu, Chen Yan, Andrew C. Newby, Arshad Rhaman, Bradford C. Berk

From the Cardiovascular Research Institute and Department of Medicine (G.G., J.A., A.M., W.L., C.Y., B.C.B.), University of Rochester, NY; Bristol Heart Institute (A.C.N.), University of Bristol, United Kingdom; and the Department of Pediatrics (A.R.), University of Rochester School of Medicine, NY.

Correspondence to Bradford C. Berk, MD, PhD, University of Rochester, Cardiovascular Research Institute, Box 679, 601 Elmwood Avenue, Rochester, NY 14642. E-mail Bradford_Berk{at}urmc.rochester.edu

Unidirectional laminar flow is atheroprotective, in part by inhibiting cytokine-mediated endothelial cell (EC) inflammation and apoptosis. Previously, we showed that flow inhibited TNF- signaling by preventing activation of JNK. Recently, PKC was identified as the PKC isoform most strongly regulated by flow pattern, with increased PKC activity in regions of disturbed flow versus unidirectional flow. Interestingly, PKC is cleaved by caspases after TNF- stimulation to generate a 50-kDa truncated form (CAT, catalytic domain of PKC) with a higher kinase activity than the full-length protein. We hypothesized that flow would inhibit TNF-–mediated PKC cleavage and thereby CAT formation. We found that PKC activity was required for TNF-–mediated JNK and caspase-3 activation in ECs. PKC was rapidly cleaved to generate CAT in cultured bovine and human aortic ECs and in intact rabbit vessels stimulated with TNF-. This truncated form of PKC enhanced JNK and caspase-3 activation. Interestingly, PKC cleavage was prevented by inhibitors of PKC, JNK, and caspase activities, suggesting that these enzymes, via regulating CAT formation, modulate caspase-3 activity in ECs. Finally, we found that flow reduced caspase-dependent processing of PKC and caspase-3 activation. These results define a novel role for PKC as a shared signaling mediator for flow and TNF-, and important for flow-mediated inhibition of proinflammatory and apoptotic events in ECs.

Key Words: endothelial cells • atypical PKC • caspase • TNF- • flow

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