Increased cardiomyocyte function and Ca2+ transients in mice during early congestive heart failure

Mørk, Halvor K.; Sjaastad, Ivar; Sande, Jørn B.; Periasamy, Muthu; Sejersted, Ole M.; Louch, William E.

doi:10.1016/j.yjmcc.2007.05.004

Cited by 45 publications

(43 citation statements)

References 39 publications

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“…This can occur on a beatto-beat basis (1) but also in the longer term by altered expression of proteins. For example, contractile function in surviving tissue after myocardial infarction is initially enhanced by augmented transsarcolemmal Ca 2+ cycling (2). We have also observed that marked enhancement of plasmalemmal Ca 2+ fluxes efficiently compensate for near-total loss of SR function after conditional Serca2 knockout (KO) (3,4).…”

mentioning

confidence: 86%

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

Swift

Franzini‐Armstrong²,

Øyehaug³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cardiomyocyte contraction and relaxation are controlled by Ca 2+ handling, which can be regulated to meet demand. Indeed, major reduction in sarcoplasmic reticulum (SR) function in mice with Serca2 knockout (KO) is compensated by enhanced plasmalemmal Ca 2+ fluxes. Here we investigate whether altered Ca 2+ fluxes are facilitated by reorganization of cardiomyocyte ultrastructure. Hearts were fixed for electron microscopy and enzymatically dissociated for confocal microscopy and electrophysiology. SR relative surface area and volume densities were reduced by 63% and 76%, indicating marked loss and collapse of the free SR in KO. Although overall cardiomyocyte dimensions were unaltered, total surface area was increased. This resulted from increased T-tubule density, as revealed by confocal images. Fourier analysis indicated a maintained organization of transverse T-tubules but an increased presence of longitudinal T-tubules. This demonstrates a remarkable plasticity of the tubular system in the adult myocardium. Immunocytochemical data showed that the newly grown longitudinal T-tubules contained Na + /Ca 2+ -exchanger proximal to ryanodine receptors in the SR but did not contain Ca 2+ -channels. Ca 2+ measurements demonstrated a switch from SR-driven to Ca 2+ influx-driven Ca 2+ transients in KO. Still, SR Ca 2+ release constituted 20% of the Ca 2+ transient in KO. Mathematical modeling suggested that Ca 2+ influx via Na + /Ca 2+ -exchange in longitudinal T-tubules triggers release from apposing ryanodine receptors in KO, partially compensating for reduced SERCA by allowing for local Ca 2+ release near the myofilaments. T-tubule proliferation occurs without loss of the original ordered transverse orientation and thus constitutes the basis for compensation of the declining SR function without structural disarrangement.excitation-contraction coupling | transgenic mice I n cardiomyocytes, Ca 2+ is cycled across the plasmalemma and across the membrane of the sarcoplasmic reticulum (SR). These two systems interact closely. Ca 2+ influx through L-type Ca 2+ channels (CaV1.2) in the T-tubules triggers Ca 2+ release from ryanodine receptors (RyR) in the SR membrane. The resulting rise in cytosolic Ca 2+ concentration elicits contraction as Ca 2+ binds to the myofilmants. Removal of Ca 2+ from the cytosol is governed by the SR calcium ATPase 2 (SERCA2), which recycles Ca 2+ into the SR, and to a lesser extent by the Na + /Ca 2+ -exchanger (NCX), which removes Ca 2+ from the cell.The two Ca 2+ cycling systems compete for Ca 2+ , and this competition can be shifted to meet demand. This can occur on a beatto-beat basis (1) but also in the longer term by altered expression of proteins. For example, contractile function in surviving tissue after myocardial infarction is initially enhanced by augmented transsarcolemmal Ca 2+ cycling (2). We have also observed that marked enhancement of plasmalemmal Ca 2+ fluxes efficiently compensate for near-total loss of SR function after conditional Serca2 knockout (KO) (3, 4). Here we report t...

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mentioning

confidence: 86%

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

Swift

Franzini‐Armstrong²,

Øyehaug³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Using this model, our laboratory has previously reported increased function in viable myocardium during early CHF with larger contractions and Ca 2ϩ transients in isolated myocytes (36,38). Importantly, Ca 2ϩ transients were observed to be slower to peak in CHF than in sham, although prolongation of the time to peak (TTP) contraction was not observed at this early stage of the disease (38). We hypothesize that prolongation of the Ca 2ϩ transient TTP and slowing of contraction are critical to deterioration of cardiac function during CHF progression.…”

Section: ϩmentioning

confidence: 99%

“…MI was induced by left coronary artery ligation in 9-wk-old female mice (C57BL/6) as previously described (36,38,53). Sham-operated animals (sham) were subjected to the same surgical procedure, without ligation of the coronary artery.…”

Section: Mouse Model Of Chf Following MImentioning

confidence: 99%

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Slowing of cardiomyocyte Ca²⁺ release and contraction during heart failure progression in postinfarction mice

Mørk

Sjaastad²,

Sejersted³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Deterioration of cardiac contractility during congestive heart failure (CHF) is believed to involve decreased function of individual cardiomyocytes and may include reductions in contraction magnitude and/or kinetics. We examined the progression of in vivo and in vitro alterations in contractile function in CHF mice and investigated underlying alterations in Ca2+ homeostasis. Following induction of myocardial infarction (MI), mice with CHF were examined at early (1 wk post-MI) and chronic (10 wk post-MI) stages of disease development. Sham-operated mice served as controls. Global and local left ventricle function were assessed by echocardiography in sedated animals (∼2% isoflurane). Excitation-contraction coupling was examined in cardiomyocytes isolated from the viable septum. CHF progression between 1 and 10 wk post-MI resulted in increased mortality, development of hypertrophy, and deterioration of global left ventricular function. Local function in the noninfarcted myocardium also declined, as posterior wall shortening velocity was reduced in chronic CHF (1.2 ± 0.1 vs. 1.9 ± 0.2 cm/s in sham). Parallel alterations occurred in isolated cardiomyocytes since contraction and Ca2+ transient time to peak values were prolonged in chronic CHF (115 ± 6 and 158 ± 11% sham values, respectively). Surprisingly, contraction and Ca2+ transient magnitudes in CHF were larger than sham values at both time points, resulting from increased sarcoplasmic reticulum Ca2+ content and greater Ca2+ influx via L-type channels. We conclude that, in mice with CHF following myocardial infarction, declining myocardial function involves slowing of cardiomyocyte contraction without reduction in contraction magnitude. Corresponding alterations in Ca2+ transients suggest that slowing of Ca2+ release is a critical mediator of CHF progression.

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“…35,36 It should be noted that the overexpression of SERCA2a at the protein level could only be achieved at B1.5. Homozygous null (SERCA2 À/À ) mice die early in development whereas heterozygous (SERCA2 +/À ) mice have been developed with a 65% decrease in SERCA2 protein levels, and although no cardiac pathology was found, when stressed by pressure overload, they developed HF much more quickly than wild-type control mice.…”

Section: Serca2a Gene Therapymentioning

confidence: 99%

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Hulot

Senyei

2012

Gene Ther

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Although progress in conventional treatments is making steady and incremental gains to reduce mortality associated with heart failure (HF), there remains a need to explore potentially new therapeutic approaches. HF induced by different etiologies such as coronary artery disease, hypertension, diabetes, infection or inflammation results generally in calcium cycling dysregulation at the myocyte level. Recent advances in understanding of the molecular basis of these calcium cycling abnormalities, together with the evolution of increasingly efficient gene transfer technology, has placed HF within the reach of gene-based therapy. Furthermore, the recent successful completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium pump ushers in a new era for gene therapy for the treatment of HF.

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Increased cardiomyocyte function and Ca2+ transients in mice during early congestive heart failure

Cited by 45 publications

References 39 publications

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

Slowing of cardiomyocyte Ca²⁺ release and contraction during heart failure progression in postinfarction mice

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

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Increased cardiomyocyte function and Ca2+ transients in mice during early congestive heart failure

Cited by 45 publications

References 39 publications

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

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Slowing of cardiomyocyte Ca²⁺ release and contraction during heart failure progression in postinfarction mice