Published online before print August 29, 2002, doi: 10.1161/01.RES.0000035242.96310.45
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Submitted on April 19, 2002
Revised on July 11, 2002
Accepted on August 15, 2002
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
Abdelkarim Sabri ;
From the Departments of Pharmacology and Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
* To whom correspondence should be addressed. E-mail: sfs1{at}columbia.edu.
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.
Key words: thrombin • protease-activated receptors • cardiac fibroblasts • epidermal growth factor receptors • signal transduction
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