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Flow Antagonizes TNF-α Signaling in Endothelial Cells by Inhibiting Caspase-Dependent PKCζ Processing
- Source :
- Circulation Research. 101:97-105
- Publication Year :
- 2007
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2007.
-
Abstract
- Unidirectional laminar flow is atheroprotective, in part by inhibiting cytokine-mediated endothelial cell (EC) inflammation and apoptosis. Previously, we showed that flow inhibited TNF-alpha signaling by preventing activation of JNK. Recently, PKCzeta was identified as the PKC isoform most strongly regulated by flow pattern, with increased PKCzeta activity in regions of disturbed flow versus unidirectional flow. Interestingly, PKCzeta is cleaved by caspases after TNF-alpha stimulation to generate a 50-kDa truncated form (CATzeta, catalytic domain of PKCzeta) with a higher kinase activity than the full-length protein. We hypothesized that flow would inhibit TNF-alpha-mediated PKCzeta cleavage and thereby CATzeta formation. We found that PKCzeta activity was required for TNF-alpha-mediated JNK and caspase-3 activation in ECs. PKCzeta was rapidly cleaved to generate CATzeta in cultured bovine and human aortic ECs and in intact rabbit vessels stimulated with TNF-alpha. This truncated form of PKCzeta enhanced JNK and caspase-3 activation. Interestingly, PKCzeta cleavage was prevented by inhibitors of PKCzeta, JNK, and caspase activities, suggesting that these enzymes, via regulating CATzeta formation, modulate caspase-3 activity in ECs. Finally, we found that flow reduced caspase-dependent processing of PKCzeta and caspase-3 activation. These results define a novel role for PKCzeta as a shared signaling mediator for flow and TNF-alpha, and important for flow-mediated inhibition of proinflammatory and apoptotic events in ECs.
- Subjects :
- Male
Physiology
medicine.medical_treatment
Inflammation
Proinflammatory cytokine
medicine
Animals
Humans
Kinase activity
Cells, Cultured
Protein Kinase C
Caspase
biology
Tumor Necrosis Factor-alpha
Endothelial Cells
Caspase Inhibitors
Cell biology
Endothelial stem cell
Cytokine
Biochemistry
Apoptosis
Caspases
biology.protein
Cattle
Rabbits
medicine.symptom
Signal transduction
Rheology
Cardiology and Cardiovascular Medicine
Blood Flow Velocity
Signal Transduction
Subjects
Details
- ISSN :
- 15244571 and 00097330
- Volume :
- 101
- Database :
- OpenAIRE
- Journal :
- Circulation Research
- Accession number :
- edsair.doi.dedup.....d95851fe9b0d509993ef4c3cdaaa2373