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

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.
Authors	Abdelkarim Sabri, Sasha G Alcott, Hasnae Elouardighi, Elena Pak, Claudia Derian, Patricia Andrade-Gordon, Kathleen Kinnally, Susan F Steinberg
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 26 Pg. 23944-54 (Jun 27 2003) ISSN: 0021-9258 [Print] United States
PMID	12707281 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Apoptosis Regulatory Proteins Carrier Proteins Intracellular Signaling Peptides and Proteins Proto-Oncogene Proteins prostate apoptosis response-4 protein Inositol 1,4,5-Trisphosphate AKT1 protein, human Akt1 protein, rat Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases Cathepsins Serine Endopeptidases CTSG protein, human Cathepsin G Ctsg protein, mouse Ctsg protein, rat
Topics	Animals Apoptosis Apoptosis Regulatory Proteins Carrier Proteins (physiology) Cathepsin G Cathepsins (physiology) Cell Adhesion Fibroblasts (metabolism) Humans Inflammation Inositol 1,4,5-Trisphosphate (metabolism) Intracellular Signaling Peptides and Proteins Mice Mice, Knockout Mitogen-Activated Protein Kinases (metabolism) Myocytes, Cardiac (cytology, metabolism) Neutrophils (enzymology) Protein Serine-Threonine Kinases Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt Rats Rats, Wistar Serine Endopeptidases p38 Mitogen-Activated Protein Kinases

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