title: Sarcoplasmic reticulum Ca2+ load in human heart failure.
abstract: Excitation-contraction coupling and intracellular Ca2+ homeostasis are altered in heart failure. We tested the hypothesis that these changes are related to disturbed Ca2+ handling of the sarcoplasmic reticulum (SR). Isolated, electrically stimulated trabeculae were obtained from end-stage failing (NYHA IV) and nonfailing human hearts. Isometric twitch tension, intracellular Ca2+ transients (aequorin method) and SR Ca2+ content (rapid cooling contractures) were assessed under basal conditions (1 Hz, 37 degrees C) as well as after stepwise increasing rest intervals from 2-240 s (post-rest contractions). Protein expression of SERCA2a and phospholamban (Western blot) was assessed in a subset of failing trabeculae. In addition, the effects of SERCA1 overexpression on contractile function of isolated myocytes was tested. On average, post-rest twitch tension continuously increased with increasing rest intervals in nonfailing, but declined with rest intervals longer than 15 s in failing myocardium. The rest-dependent contractile changes were accompanied by parallel changes in intracellular Ca2+ transients. Failing trabeculae (n = 40) were grouped (group A: post-rest potentiation (force of contraction > pre-rest twitch force) after 120 s rest interval; group B: post-rest decay (force of contraction < pre-rest twitch force) after 120 s rest interval), and post-rest contractile function was related to SERCA2a and PLB expression. While PLB protein expression was not different, SERCA2a protein expression as well as SERCA2a/PLB ratio was significantly higher in group A vs. group B. Transfection of SERCA1 increased shortening amplitude and enhanced relaxation kinetics in failing human myocytes. In conclusion, SR Ca2+ handling is severely altered in human heart failure. Reduced SR Ca2+ release is due to diminished SR Ca2+ content directly related to a depressed expression of SERCA2a protein. Enhancing SERCA function or expression may improve SR Ca2+ handling in failing human myocardium.
authors.affiliation: Labor für Molekulare Kardiologie und Herzmuskelphysiologie, Abteilung Kardiologie und Angiologie, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37085 Göttingen, Germany. pieske@med.uni-goettingen.de
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt-Schweda
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002303:Cardiac Output, Low / Q000378:metabolism* / Q000503:physiopathology; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000502:physiology; D012016:Reference Values; D012146:Rest; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C506943:ATP2A1 protein, human