{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T15:50:34Z","timestamp":1772898634073,"version":"3.50.1"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[1998,3,9]]},"abstract":"<jats:p><jats:italic>Abstract<\/jats:italic>\u2014Cytotoxic T lymphocytes (CTLs) that infiltrate 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 Fas ligand, we explored the interaction between peritoneal exudate CTLs (PELs), derived from perforin gene\u2013knockout (P\u2212\/\u2212) mice, and murine ventricular myocytes. Fas expression on isolated ventricular myocytes was demonstrated immunohistochemically. Action potentials, [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>transients, and contractions of myocytes conjugated to P\u2212\/\u2212 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\u2212\/\u2212 PELs were, respectively, as follows: V<jats:sub>m<\/jats:sub>, \u221273.2\u00b11.5 and \u221253.6\u00b16.4 mV (mean\u00b1SEM); action potential amplitude, 117.9\u00b13.9 and 74.3\u00b121.2 mV; and action potential duration at 80% repolarization, 17\u00b16 and 42\u00b113 milliseconds (all<jats:italic>P<\/jats:italic>&lt;.05). P\u2212\/\u2212 PELs also induced early and delayed afterdepolarizations as well as arrhythmogenic activity. Diastolic [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increased during the cytocidal interaction with P\u2212\/\u2212 PELs, from a fluorescence ratio of 0.82\u00b10.05 (n=7) to 1.98\u00b10.09 (n=13) (<jats:italic>P<\/jats:italic>&lt;.05). All of the effects caused by P\u2212\/\u2212 PELs were reproduced by incubating the myocytes with Jo2. Heparin (50 \u03bcg\/mL), an antagonist of inositol trisphosphate (IP<jats:sub>3<\/jats:sub>)\u2013operated sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>channels, or U-73122 (2 \u03bcmol\/L), a phospholipase C inhibitor, but not the inactive agonist U-73343, prevented Fas-mediated myocyte dysfunction. Additionally, intracellular application (through the patch pipette) of the active IP<jats:sub>3<\/jats:sub>analogue, inositol 1,4,5-trisphosphate, but not the inactive analogue, inositol 1,3,4-trisphosphate, caused electrophysiological changes resembling those resulting from P\u2212\/\u2212 PELs and Jo2, suggesting that CTL-induced Fas-based myocyte dysfunction is mediated by IP<jats:sub>3<\/jats:sub>. We conclude that a Fas-based perforin-independent mechanism of CTL action can account for the immunopathology seen in the allotransplanted heart, myocarditis, and dilated cardiomyopathy.<\/jats:p>","DOI":"10.1161\/01.res.82.4.438","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:47:05Z","timestamp":1339462025000},"page":"438-450","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":60,"title":["Fas (CD95\/Apo-1)\u2013Mediated Damage to Ventricular Myocytes Induced by Cytotoxic T Lymphocytes From Perforin-Deficient Mice"],"prefix":"10.1161","volume":"82","author":[{"given":"Bella","family":"Felzen","sequence":"first","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Shilkrut","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hadar","family":"Less","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Israel","family":"Sarapov","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gila","family":"Maor","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond","family":"Coleman","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard B.","family":"Robinson","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gideon","family":"Berke","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; the Department of Heart Surgery (I.S.), Carmel Medical Center, Haifa, Israel; the Department of Pharmacology (R.B.R.), College of Physicians &amp; Surgeons of Columbia University, New York, NY; and the Department of Immunology (G.B.), Weizmann Institute..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ofer","family":"Binah","sequence":"additional","affiliation":[{"name":"From the Rappaport Family Institute for Research in the Medical Sciences (B.F., M.S., H.L., G.M., R.C., O.B.), Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa, Israel; 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