Excitation-contraction coupling and intracellular Ca$^2+$ homeostasis
are altered in heart failure. We tested the hypothesis that these
changes are related to disturbed Ca$^2+$ 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 Ca$^2+$ transients
(aequorin method) and SR Ca$^2+$ 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
Ca$^2+$ 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 Ca$^2+$ handling is severely altered in human
heart failure. Reduced SR Ca$^2+$ release is due to diminished
SR Ca$^2+$ content directly related to a depressed expression
of SERCA2a protein. Enhancing SERCA function or expression may improve
SR Ca$^2+$ handling in failing human myocardium.
%0 Journal Article
%1 Pies_2002_I63
%A Pieske, Burkert
%A Maier, Lars S
%A Schmidt-Schweda, Stephan
%D 2002
%J Basic Res. Cardiol.
%K 12479237 ATPase, Calcium, Calcium-Binding Cardiac Contraction, Gov't, Heart, Humans, In Low, Myocardial Non-U.S. Output, Proteins, Reference Research Rest, Reticulum, Sarcoplasmic Support, Values, Vitro, {C}a$^{2+}$-Transporting
%P I63--I71
%T Sarcoplasmic reticulum Ca$^2+$ load in human heart failure.
%V 97 Suppl 1
%X Excitation-contraction coupling and intracellular Ca$^2+$ homeostasis
are altered in heart failure. We tested the hypothesis that these
changes are related to disturbed Ca$^2+$ 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 Ca$^2+$ transients
(aequorin method) and SR Ca$^2+$ 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
Ca$^2+$ 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 Ca$^2+$ handling is severely altered in human
heart failure. Reduced SR Ca$^2+$ release is due to diminished
SR Ca$^2+$ content directly related to a depressed expression
of SERCA2a protein. Enhancing SERCA function or expression may improve
SR Ca$^2+$ handling in failing human myocardium.
@article{Pies_2002_I63,
abstract = {Excitation-contraction coupling and intracellular {C}a$^{2+}$ homeostasis
are altered in heart failure. We tested the hypothesis that these
changes are related to disturbed {C}a$^{2+}$ 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 {C}a$^{2+}$ transients
(aequorin method) and SR {C}a$^{2+}$ 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
{C}a$^{2+}$ 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 {C}a$^{2+}$ handling is severely altered in human
heart failure. Reduced SR {C}a$^{2+}$ release is due to diminished
SR {C}a$^{2+}$ content directly related to a depressed expression
of SERCA2a protein. Enhancing SERCA function or expression may improve
SR {C}a$^{2+}$ handling in failing human myocardium.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Pieske, Burkert and Maier, Lars S and Schmidt-Schweda, Stephan},
biburl = {https://www.bibsonomy.org/bibtex/2b51c38e0f7918834315ff99343a0dd68/hake},
description = {The whole bibliography file I use.},
file = {Pies_2002_I63.pdf:Pies_2002_I63.pdf:PDF},
interhash = {f621e70f7b268a726f85345635d680f8},
intrahash = {b51c38e0f7918834315ff99343a0dd68},
journal = {Basic Res. Cardiol.},
keywords = {12479237 ATPase, Calcium, Calcium-Binding Cardiac Contraction, Gov't, Heart, Humans, In Low, Myocardial Non-U.S. Output, Proteins, Reference Research Rest, Reticulum, Sarcoplasmic Support, Values, Vitro, {C}a$^{2+}$-Transporting},
pages = {I63--I71},
pmid = {12479237},
timestamp = {2009-06-03T11:21:25.000+0200},
title = {Sarcoplasmic reticulum {C}a$^{2+}$ load in human heart failure.},
volume = {97 Suppl 1},
year = 2002
}