Activated protein C (APC) has anti-inflammatory and vascular protective effects independent of anticoagulation. We previously identified the prototypical thrombin receptor, protease-activated receptor-1 (PAR1), as part of a novel APC-endothelial cell protein C receptor ( EPCR) signaling pathway in endothelial cells. Experiments in wild-type and PAR1(-/-) mice demonstrated that intravenous injection of APC leads to PAR1-dependent gene induction in the lung. The vascular endothelium undergoes profound changes in severe sepsis, the approved therapeutic indication for APC. Similar to PAR1, APC activated PAR2 through canonical cleavage. Although PAR2 was up-regulated in cytokine-stimulated endothelial cells, APC signaling remained PAR1-dependent. Large scale gene expression profiling documented marked differences in both up- and down-regulated genes between APC and thrombin signaling in cytokine-stimulated cells. APC down-regulated transcripts for proapoptotic proteins including p53 and thrombospondin-1, but p53 was unchanged, and thrombospondin was even upregulated by thrombin. Concordant PAR1-dependent effects on protein levels were found. Thus, by signaling through the same receptor PAR1, APC, and thrombin can exert distinct biological effects in perturbed endothelium. These data may explain how APC can be therapeutically protective through the EPCR-PAR1 signaling despite ongoing thrombin generation due to disseminated intravascular coagulopathy.
机构:
Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Camerer, E
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Kataoka, H
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Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Kataoka, H
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Kahn, M
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Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Kahn, M
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Lease, K
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Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Lease, K
;
Coughlin, SR
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Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Cheng, T
;
Liu, D
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机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Liu, D
;
Griffin, JH
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机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Griffin, JH
;
Fernández, JA
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机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Fernández, JA
;
Castellino, F
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机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Castellino, F
;
Rosen, ED
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机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Rosen, ED
;
Fukudome, K
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机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Fukudome, K
;
Zlokovic, BV
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Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USAUniv Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
机构:
Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Camerer, E
;
Kataoka, H
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h-index: 0
机构:
Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Kataoka, H
;
Kahn, M
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h-index: 0
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Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Kahn, M
;
Lease, K
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h-index: 0
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Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
Lease, K
;
Coughlin, SR
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Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Cheng, T
;
Liu, D
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机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Liu, D
;
Griffin, JH
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h-index: 0
机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Griffin, JH
;
Fernández, JA
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h-index: 0
机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Fernández, JA
;
Castellino, F
论文数: 0引用数: 0
h-index: 0
机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Castellino, F
;
Rosen, ED
论文数: 0引用数: 0
h-index: 0
机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Rosen, ED
;
Fukudome, K
论文数: 0引用数: 0
h-index: 0
机构:Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA
Fukudome, K
;
Zlokovic, BV
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h-index: 0
机构:
Univ Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USAUniv Rochester, Med Ctr, Frank P Smith Neurosurg Res Lab, Dept Neurosurg, Rochester, NY 14642 USA