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

被引:96
作者
Sabri, A
Short, J
Guo, JF
Steinberg, SF
机构
[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
关键词
thrombin; protease-activated receptors; cardiac fibroblasts; epidermal growth factor receptors; signal transduction;
D O I
10.1161/01.RES.0000035242.96310.45
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:532 / 539
页数:8
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