Fas (CD95/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice: A major role for inositol 1,4,5-trisphosphate

Abstract

Cytotoxic T lymphocytes (CTLs)that infaltrate the heart are important immune effectors implicated in heart transplant rejection myocarditis, and other cardiomyopathies. To investigate the mechanism(s) underlying CTL damage to the myocardium through activation of the Fas receptor (Fas/CD95/Apo-1) by the Far ligand, we explored the toteraction between peritoneal exudate CTLs (PELs), derived from perform gene-knockout (P-/-) mice, and murine ventricular myocytes. Fas expression on isolated ventricular myocytes was demonstrated immunohistochemically. Action potentials, [Ca2+](i) transients, and contractions of myocytes conjugated to P-/- PELs or treated with the apoptosis-inducing anti-Fas monoclonal antibody Jo2 were recorded. Action potential characteristics of nonconjugated myocytes and myocytes conjugated with P-/- PELs were, respectively, as follows: V(m), -73.2±1.5 and -53.6±6.4 mV (mean±SEM); action potential amplitude, 117.9±3.9 and 74.3±21.2 mV; and action potential duration at 80% repolarization, 17±6 and 42±13 milliseconds (all P