Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation.

Luo, Wusheng; Grupp, Ingrid L.; Harrer, Judy M.; Ponniah, Sathivel; Grupp, Günter; Duffy, John; Doetschman, Thomas; Kranias, Evangelia G.

doi:10.1161/01.res.75.3.401

Cited by 636 publications

(559 citation statements)

References 46 publications

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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

218

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

218

183

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“…They showed that absence of PLB enhanced SR calcium uptake and increased rates of contraction and relaxation. This was associated with an increase in SERCA2a affinity for calcium [41]. On the other hand, over-expression of PLB in the heart resulted in a decrease in SR Ca 2+ uptake and depressed cardiac contractile performance in vivo.…”

Section: Transgenic Approaches To Study the Role Of Plb And Sln In Camentioning

confidence: 97%

“…Studies using genetically altered mouse models have given important insight into the role of PLB in cardiac physiology. Using a PLB knockout mouse model [41], Dr. Kranias and colleagues provided the crucial evidence that PLB is an important regulator of the SERCA2a. They showed that absence of PLB enhanced SR calcium uptake and increased rates of contraction and relaxation.…”

Section: Transgenic Approaches To Study the Role Of Plb And Sln In Camentioning

confidence: 99%

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Bhupathy¹,

Babu²,

Periasamy³

2007

Journal of Molecular and Cellular Cardiology

119

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The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a critical role in maintaining the intracellular calcium homeostasis during cardiac contraction and relaxation. It has been well documented over the years that altered expression and activity of SERCA2a can lead to systolic and diastolic dysfunction. The activity of SERCA2a is regulated by two structurally similar proteins, phospholamban (PLB) and sarcolipin (SLN). Although, the relevance of PLB has been extensively studied over the years, the role SLN in cardiac physiology is an emerging field of study. This review focuses on the advances in the understanding of the regulation of SERCA2a by SLN and PLB. In particular, it highlights the similarities and differences between the two proteins and their roles in cardiac patho-physiology.

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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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Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation.

Cited by 636 publications

References 46 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Rodent models of heart failure: an updated review

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