title: Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes.
abstract: During early apoptosis, adult cardiomyocytes show unusual beating, suggesting possible participation of abnormal Ca(2+) transients in initiation of apoptotic processes in this cell type. Simultaneously with the beating, these cells show dynamic structural alteration resulting from cytoskeletal disintegration that is quite rapid. Because of the specialized structure and extensive cytoskeleton of cardiomyocytes, we hypothesized that its degradation in so short a time would require a particularly efficient mechanism. To better understand this mechanism, we used serial video microscopy to observe beta-adrenergic stimulation-induced apoptosis in isolated adult rat cardiomyocytes while simultaneously recording intracellular Ca(2+) concentration and cell length. Trains of Ca(2+) transients and corresponding rhythmic contractions and relaxations (beating) were observed in apoptotic cells. Frequencies of Ca(2+) transients and beating gradually increased with time and were accompanied by cellular shrinkage. As the cells shrank, amplitudes of Ca(2+) transients declined and diastolic intracellular Ca(2+) concentration increased until the transients were lost. Beating and progression of apoptosis were significantly inhibited by antagonists against the L-type Ca(2+) channel (nifedipine), ryanodine receptor (ryanodine), inositol 1,4,5-trisphosphate receptor (heparin), sarco(endo)plasmic Ca(2+)-ATPase (thapsigargin), and Na(+)/Ca(2+) exchanger (KB-R7943). Electron-microscopic examination of beating cardiomyocytes revealed progressive breakdown of Z disks. Immunohistochemical analysis and Western blot confirmed that disappearance of Z disk constituent proteins (alpha-actinin, desmin, and tropomyosin) preceded degradation of other cytoskeletal proteins. It thus appears that, in adult cardiomyocyte apoptosis, Ca(2+) transients mediate apoptotic beating and efficient sarcomere destruction initiated by Z disk breakdown.
authors.affiliation: Second Dept. of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Noritsugu
authors.initials: N
authors.lastname: Tohse
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkusa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Masunori
authors.initials: M
authors.lastname: Matsuzaki
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010507:Periodicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*
chemical_list: D000318:Adrenergic beta-Agonists; D007545:Isoproterenol; D002118:Calcium