Chronic Phospholamban–Sarcoplasmic Reticulum Calcium ATPase Interaction Is the Critical Calcium Cycling Defect in Dilated Cardiomyopathy

Minamisawa, Susumu; Hoshijima, Masahiko; Chu, Guoxiang; Ward, Christopher A.; Frank, Konrad; Gu, Yusu; Martone, Maryann E.; Wang, Yibin; Ross, John; Kranias, Evangelia G.; Giles, Wayne R.; Chien, Kenneth R.

doi:10.1016/s0092-8674(00)81662-1

Cited by 469 publications

(375 citation statements)

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“…13) without activating receptor-mediated pathways (e. g., β-adrenergic receptors) could be promising. In experimental heart failure models, transgenic inhibition or deletion of phospholamban [51, 116,134] or adenoviral increase of SR Ca 2+ -ATPase expression [52] frequently, but not always [185], improved LV function and survival. Interestingly, the increase of SR Ca 2+ -ATPase expression was associated with an improvement of the PCr/ATP ratio in rats with heart failure after aortic banding [52], supporting the hypothesis that reconstitution of EC coupling may improve energetics.…”

Section: Discussionmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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Section: Discussionmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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“…Increased contractility [170] Preserves cardiac contractility and left ventricular chamber size close to normal in MLP-deficient mice [193] Restoring expression of S100A1 to normal levels in post-MI rats improved LV function and reduced LV dilation S100A1 [229] Overexpression…”

Section: General Considerationsmentioning

confidence: 99%

Rodent models of heart failure: an updated review

et al. 2012

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Heart failure (HF) is one of the major health and economic burdens worldwide, and its prevalence is continuously increasing. The study of HF requires reliable animal models to study the chronic changes and pharmacologic interventions in myocardial structure and function and to follow its progression toward HF. Indeed, during the past 40 years, basic and translational scientists have used small animal models to understand the pathophysiology of HF and find more efficient ways of preventing and managing patients suffering from congestive HF (CHF). Each species and each animal model has advantages and disadvantages, and the choice of one model over another should take them into account for a good experimental design. The aim of this review is to describe and highlight the advantages and drawbacks of some commonly used HF rodents models, including both non-genetically and genetically engineered models, with a specific subchapter concerning diastolic HF models.

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“…By mating the Tm180 mice with the PLN KO mice, we rescued the resulting progeny (PLN KO/ Tm180 mice) from the disease parameters manifest in the hypertrophic cardiomyopathy phenotype (7). This rescue occurs by modulating SR calcium cycling, an approach previously used in other models of cardiomyopathy (3,12,19).…”

Section: Discussionmentioning

confidence: 99%

“…The resulting double transgenic mice were phenotypically rescued, showing a normal heart size and morphology, significantly improved cardiac function, and normal myofilament calcium sensitivity. Also, studies demonstrate that hypertrophy and cardiac dysfunction can be improved by ablation of PLN in various animal models (3,7,12,19). In addition, gene transfer of SERCA2a into the Tm180 neonates also improves cardiac hypertrophy and hemodynamic performance (13).…”

Section: Discussionmentioning

confidence: 99%

Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

Rajan

Peña

Jegga

et al. 2013

Physiological Genomics

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Rajan S, Pena JR, Jegga AG, Aronow BJ, Wolska BM, Wieczorek DF. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics 45: 764 -773, 2013. First published June 25, 2013 doi:10.1152/physiolgenomics.00023.2013.-Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHCassociated mutation in ␣-tropomyosin: Glu ¡ Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype. tropomyosin; phospholamban; cardiomyopathy; mouse model CARDIOVASCULAR DISEASE IS the leading cause of mortality in the Western world, with heart failure representing one of the fastest growing subgroups over the past decade. Systolic and diastolic dysfunction is common in patients suffering from many types of heart disease and cardiac failure. In addition, hypertrophic growth of cardiomyocytes occurs in many forms of heart failure and may contribute to the pathogenesis of the failure state.Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in contractile proteins of the cardiac sarcomere, Z-disc proteins, and Ca 2ϩ -handling proteins (5). ␣-tropomyosin (Tm), a thin filament protein of the sarcomere, has been found to encode 11 mutations that lead to FHC (23). Previous work in our laboratories established a transgenic mouse model expressing mutant FHC Tm180 protein (1,7,16,17). This mouse develops severe concentric cardiac hypertrophy with si...

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Chronic Phospholamban–Sarcoplasmic Reticulum Calcium ATPase Interaction Is the Critical Calcium Cycling Defect in Dilated Cardiomyopathy

Cited by 469 publications

References 46 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

Rodent models of heart failure: an updated review

Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

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