title: Load-dependent induction of apoptosis in multicellular myocardial preparations.
abstract: Increased mechanical load has been proposed as an inductor of apoptosis, but it is unknown whether this can occur in the range of pre- and afterloads that prevail in the beating heart. We investigated apoptosis in cultured rabbit multicellular myocardial preparations over several days. Muscles contracted in absence of pre- and afterload (unloaded isotonic), in absence of preload but in presence of afterload (unloaded isometric), or in presence of both (loaded isometric). After up to 48 h of continuous contractions, apoptosis was assessed by TdT-mediated nick-end labeling (TUNEL) assay and DNA ladder analysis. In muscles that contracted loaded isometric, apoptosis was detected after 6-24 h. After 48 h, apoptosis was most prominent in this group, reflected by a high level of DNA ladder intensity (DLI; 27.8 +/- 11.5), whereas Bcl-xL (on RNA level) was significantly downregulated, and Fas remained unchanged. In unloaded isometric preparations, apoptosis was significantly less (6.9 +/- 5.9 DLI) and very similar to those contracting unloaded isotonic (6.1 +/- 5.1 DLI). We conclude that load-dependent apoptosis can occur at sarcomere lengths achievable in vivo and may mainly result from increased preload.
authors.affiliation: Abteilung Kardiologie und Pneumologie, Universität Göttingen, Göttingen D-37075, Germany. pjanssen@jhmi.edu
authors.forename: P M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: G
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: O
authors.initials: O
authors.lastname: Zeitz
authors.forename: S E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: J
authors.initials: J
authors.lastname: Prestle
authors.forename: D
authors.initials: D
authors.lastname: Darmer
authors.forename: J
authors.initials: J
authors.lastname: Holtz
authors.forename: H
authors.initials: H
authors.lastname: Schumann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006321:Heart / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D007537:Isometric Contraction / Q000502:physiology; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016474:Weight-Bearing / Q000502:physiology*; D051020:bcl-X Protein; D019014:fas Receptor / Q000235:genetics
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases