Protease-activated receptor-1-mediated DNA synthesis in cardiac fibroblast is via epidermal growth factor receptor transactivation - Distinct PAR-1 signaling pathways in cardiac fibroblasts and cardiomyocytes
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作者:
Sabri, A
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机构:Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
Sabri, A
Short, J
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机构:Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
Short, J
Guo, JF
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机构:Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
Guo, JF
Steinberg, SF
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机构:Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
Steinberg, SF
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[1] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA
Proteases elaborated by inflammatory cells in the heart would be expected to drive cardiac fibroblasts to proliferate, but protease-activated receptor (PAR) function in cardiac fibroblasts has never been considered. This study demonstrates that PAR-1 is the only known PAR family member functionally expressed by cardiac fibroblasts and that PAR-1 activation by thrombin leads to increased DNA synthesis in cardiac fibroblasts. The increase in DNA synthesis induced by PAR-1 substantially exceeds the effects of other G protein-coupled receptor agonists in this cell type. PAR-1 stimulates phosphoinositide hydrolysis and mobilizes intracellular calcium via pertussis toxin (PTX)-sensitive and PTX-insensitive pathways. Activation of PAR-1 leads to an increase in Src, Fyn, and epidermal growth factor receptor (EGFR) phosphorylation, with EGFR receptor transactivation by Src family kinases the major mechanism for PAR-1-dependent activation of extracellular signal-regulated kinase, p38-mitogen-activated protein kinase, and protein kinase B. Activation of PAR-1 also leads to an increase in DNA synthesis. PAR-1 signaling is highly contextual in nature, inasmuch as PAR-1 activates extracellular signal-regulated kinase and only weakly stimulates protein kinase B via a pathway that does not involve EGFR transactivation in cardiomyocytes. PAR-1 responses in cardiac fibroblasts and cardiomyocytes are predicted to contribute importantly to remodeling during cardiac injury and/or inflammation.
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Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia
Crouch, MF
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Davy, DA
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Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia
Davy, DA
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Willard, FS
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Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia
Willard, FS
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Berven, LA
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Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia
机构:
Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia
Crouch, MF
;
Davy, DA
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Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia
Davy, DA
;
Willard, FS
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Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia
Willard, FS
;
Berven, LA
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机构:
Australian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, AustraliaAustralian Natl Univ, John Curtin Sch Med Res, Div Neurosci, Mol Signalling Grp, Canberra, ACT 2601, Australia