Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism

Abdelkarim Sabri, Sasha G. Alcott, Hasnae Elouardighi, Elena Pak, Claudia Derian, Patricia Andrade-Gordon, Kathleen Kinnally, Susan F. Steinberg

Research output: Contribution to journalArticle

Abstract

Cathepsin G is a neutrophil-derived serine protease that contributes to tissue damage at sites of inflammation. The actions of cathepsin G are reported to be mediated by protease-activated receptor (PAR)-4 (a thrombin receptor) in human platelets. This study provides the first evidence that cathepsin G promotes inositol 1,4,5-trisphosphate accumulation, activates ERK, p38 MAPK, and AKT, and decreases contractile function in cardiomyocytes. Because some cathepsin G responses mimic cardiomyocyte activation by thrombin, a role for PARs was considered. Cathepsin G markedly activates phospholipase C and p38 MAPK in cardiomyocytes from PAR-1-/- mice, but it fails to activate phospholipase C, ERK, p38 MAPK, or AKT in PAR-1- or PAR-4-expressing PAR-1-/- fibroblasts (which display robust responses to thrombin). These results argue that PAR-1 does not mediate the actions of cathepsin G in cardiomyocytes, and neither PAR-1 nor PAR-4 mediates the actions of cathepsin G in fibroblasts. Of note, prolonged incubation of cardiomyocytes with cathepsin G results in the activation of caspase-3, cleavage of FAK and AKT, sarcomeric disassembly, cell rounding, cell detachment from underlying matrix, and morphologic features of apoptosis. Inhibition of Src family kinases or caspases (with PP1 or benzyloxycarbonyl-VAD-fluoromethyl ketone, respectively) delays FAK and AKT cleavage and cardiomyocyte detachment from substrate. Collectively, these studies describe novel cardiac actions of cathepsin G that do not require PARs and are predicted to assume functional importance at sites of interstitial inflammation in the heart.

Original languageEnglish (US)
Pages (from-to)23944-23954
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number26
DOIs
StatePublished - Jul 27 2003

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Proteinase-Activated Receptors
Cathepsin G
Cardiac Myocytes
Neutrophils
PAR-1 Receptor
Apoptosis
p38 Mitogen-Activated Protein Kinases
Type C Phospholipases
Fibroblasts
Thrombin
Chemical activation
Thrombin Receptors
Inflammation
Inositol 1,4,5-Trisphosphate
src-Family Kinases
Serine Proteases
Caspases
Platelets
Ketones
Caspase 3

ASJC Scopus subject areas

  • Biochemistry

Cite this

Sabri, A., Alcott, S. G., Elouardighi, H., Pak, E., Derian, C., Andrade-Gordon, P., ... Steinberg, S. F. (2003). Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism. Journal of Biological Chemistry, 278(26), 23944-23954. https://doi.org/10.1074/jbc.M302718200

Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism. / Sabri, Abdelkarim; Alcott, Sasha G.; Elouardighi, Hasnae; Pak, Elena; Derian, Claudia; Andrade-Gordon, Patricia; Kinnally, Kathleen; Steinberg, Susan F.

In: Journal of Biological Chemistry, Vol. 278, No. 26, 27.07.2003, p. 23944-23954.

Research output: Contribution to journalArticle

Sabri, A, Alcott, SG, Elouardighi, H, Pak, E, Derian, C, Andrade-Gordon, P, Kinnally, K & Steinberg, SF 2003, 'Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism', Journal of Biological Chemistry, vol. 278, no. 26, pp. 23944-23954. https://doi.org/10.1074/jbc.M302718200
Sabri, Abdelkarim ; Alcott, Sasha G. ; Elouardighi, Hasnae ; Pak, Elena ; Derian, Claudia ; Andrade-Gordon, Patricia ; Kinnally, Kathleen ; Steinberg, Susan F. / Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 26. pp. 23944-23954.
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