title: Calcium paradox induces apoptosis in the isolated perfused Rana ridibunda heart: involvement of p38-MAPK and calpain.
abstract: "Calcium paradox" as a term describes the deleterious effects conferred to a heart perfused with a calcium-free solution followed by repletion, including loss of mechanical activity and sarcomere disruption. Given that the signaling mechanisms triggered by calcium paradox remain elusive, in the present study, we tried to investigate them in the isolated perfused heart from Rana ridibunda. Calcium paradox was found to markedly activate members of the MAPKs (p43-ERK, JNKs, p38-MAPK). In addition to lactate dehydrogenase (LDH) release in the perfusate (indicative of necrosis), we also confirmed the occurrence of apoptosis by using the TUNEL assay and identifying poly(ADP-ribose) polymerase (PARP) fragmentation and upregulated Bax expression. Furthermore, using MDL28170 (a selective calpain inhibitor), a role for this protease was revealed. In addition, various divalent cations were shown to exert a protective effect against the calcium paradox. Interestingly, SB203580, a p38-MAPK inhibitor, alleviated calcium-paradox-conferred apoptosis. This result indicates that p38-MAPK plays a pro-apoptotic role, contributing to the resulting myocardial dysfunction and cell death. To our knowledge, this is the first time that the calcium paradox has been shown to induce apoptosis in amphibians, with p38-MAPK and calpain playing significant roles.
authors.affiliation: Department of Animal and Human Physiology, School of Biology, University of Athens, University campus, Athens, 157 84, Greece.
authors.forename: Ioanna-Katerina
authors.initials: IK
authors.lastname: Aggeli
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Zacharias
authors.forename: Georgia
authors.initials: G
authors.lastname: Papapavlou
authors.forename: Catherine
authors.initials: C
authors.lastname: Gaitanaki
authors.forename: Isidoros
authors.initials: I
authors.lastname: Beis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D006321:Heart / Q000503:physiopathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011895:Rana ridibunda / Q000378:metabolism* / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051028:bcl-2-Associated X Protein; D007770:L-Lactate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D002154:Calpain; D002118:Calcium