Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes

Details

Ressource 1Download: serval:BIB_3403BB84961D.P001 (1107.66 [Ko])
State: Public
Version: author
License: Not specified
It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
Serval ID
serval:BIB_3403BB84961D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes
Journal
Cardiovascular Research
Author(s)
Felzen  B., Berke  G., Rosen  D., Coleman  R., Tschopp  J., Young  J. D., Binah  O.
ISSN
0008-6363 (Print)
Publication state
Published
Issued date
05/1994
Volume
28
Number
5
Pages
643-9
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S. --- Old month value: May
Abstract
OBJECTIVE: Involvement of cytotoxic T lymphocytes (CTL) in heart transplant rejection as well as in viral myocarditis is well established, but the precise mechanisms whereby infiltrating CTL damage the myocardium are unknown. The aim of the study was to investigate how CTL derived perforin, the serine protease granzyme A, and the combination of both, damage guinea pig ventricular myocytes. METHODS: Action potentials and membrane currents were recorded by means of the whole cell configuration from guinea pig ventricular myocytes. RESULTS: Resembling the effects of CTL derived lytic granules, perforin caused gradual myocyte shortening and contracture, leading to complete loss of the rod shaped morphology and to cell destruction. These changes were preceded by shortening of action potential duration and reduction of resting potential and action potential amplitude, followed by complete inexcitability. Granzyme A alone was ineffective, but accelerated the deleterious effects of perforin on the morphological and electrophysiological properties of myocytes. The effects of perforin were further evaluated by measuring membrane currents by means of the whole cell voltage clamp. Perforin induced discrete changes in membrane current, reminiscent of single ion channels, with large conductance and open time of up to several seconds. Linear regression analysis of the channel I-V relations resulted in a conductance of 890 pS and a reversal potential of -7.6 mV. These results suggest that perforin induces large non-selective channels, which can account for most of the observed adverse effects. CONCLUSIONS: As CTL participate in the immunological rejection of the transplanted heart, it is conceivable, but remains to be shown, that part of this damage is inflicted by perforin containing lytic granules.
Keywords
Action Potentials/drug effects Animals Calcium/pharmacology Cells, Cultured Granzymes Guinea Pigs Heart Ventricles/cytology/*drug effects/physiology Ion Channels/drug effects Membrane Glycoproteins/*pharmacology Membrane Potentials/drug effects Pore Forming Cytotoxic Proteins Serine Endopeptidases/*pharmacology *T-Lymphocytes, Cytotoxic
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 16:19
Last modification date
01/10/2019 7:17
Usage data