Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes

Piacentino, Valentino; Weber, Christopher R.; Chen, Xiongwen; Weisser-Thomas, Jutta; Margulies, Kenneth B.; Bers, Donald M.; Houser, Steven R.

doi:10.1161/01.res.0000062469.83985.9b

Cited by 436 publications

(400 citation statements)

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“…A major deficit in failing myocytes is the reduced Ca 2+ content of the SR, which is related to decreased expression and activity of the SR Ca 2+ -ATPase [84,92,146,153] and an increased Ca 2+ leak of the RyR2 due to hyperphosphorylation [84,94,112,122]. These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184], lead to a smaller and more dyssynchronous SR Ca 2+ release during an AP, resulting in slower rates of increase and decay of [Ca 2+ ] c , but higher diastolic [Ca 2+ ] c compared to normal cardiac myocytes [17,81,113,115,146,184].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212]. In this context, the elevation of [Na + ] i in cardiac failure and hypertrophy may be regarded as a beneficial and compensatory mechanism [94].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212] Are defects in EC coupling linked to energy starvation in heart failure?Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

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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: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

mentioning

confidence: 99%

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Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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“…Deteriorated function of the failing heart has been partially attributed to dysfunction of the phospholamban (PLB)-controlled sarcoplasmic reticulum Ca 2+ pump (SERCA2a). 1 Reduction of both SERCA2a expression and PLB phosphorylation 2,3 may contribute to this dysfunction. Non-phosphorylated PLB keeps the Ca 2+ affinity of SERCA2a low, resulting in decreased sarcoplasmic reticulum (SR) Ca 2+ uptake, slowed relaxation and decreased SR Ca 2+ load, whereas PLB phosphorylation in response to b-adrenergic stimulation relieves this inhibition.…”

Section: Introductionmentioning

confidence: 99%

Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban

et al. 2006

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Impaired function of the phospholamban (PLB)-regulated sarcoplasmic reticulum Ca 2+ pump (SERCA2a) contributes to cardiac dysfunction in heart failure (HF). PLB downregulation may increase SERCA2a activity and improve cardiac function. Small interfering (si)RNAs mediate efficient gene silencing by RNA interference (RNAi). However, their use for in vivo gene therapy is limited by siRNA instability in plasma and tissues, and by low siRNA transfer rates into target cells. To address these problems, we developed an adenoviral vector (AdV) transcribing short hairpin (sh)RNAs against rat PLB and evaluated its potential to silence the PLB gene and to modulate SERCA2a-mediated Ca 2+ sequestration in primary neonatal rat cardiomyocytes (PNCMs). Over a period of 13 days, vector transduction resulted in stable 499.9% ablation of PLB-mRNA at a multiplicity of infection of 100. PLB protein gradually decreased until day 7 (772% left), whereas SERCA, Na + / Ca 2+ exchanger (NCX1), calsequestrin and troponin I protein remained unchanged. PLB silencing was associated with a marked increase in ATP-dependent oxalate-supported Ca 2+ uptake at 0.34 mM of free Ca 2+ , and rapid loss of responsiveness to protein kinase A-dependent stimulation of Ca 2+ uptake was maintained until day 7. In summary, these results indicate that AdV-derived PLB-shRNA mediates highly efficient, specific and stable PLB gene silencing and modulation of active Ca 2+ sequestration in PNCMs. The availability of the new vector now enables employment of RNAi for the treatment of HF in vivo.

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“…Gene expression reverts to an immature state, including down-regulation of α-myosin heavy chain (MHC) concurrent with up-regulation of β-MHC, reminiscent of the relative expression levels of these motor proteins in the embryonic heart (8,9). Functionally, myocytes isolated from failing hearts show defective excitationcontraction coupling (10), including reduced calcium uptake into the sarcoplasmic reticulum (11). Contractile function is also reduced, as shown by decreased cardiac output in dogs subjected to chronic rapid pacing (12) and decreased tension in left ventricular strips isolated from failing human myocardium (13,14).…”

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confidence: 99%

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

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

139

124

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The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structurefunction relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α-to β-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart. organs on chips | mechanotransduction | muscular thin films | microarray | contraction

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Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes

Abstract: Abstract-Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca 2ϩ

Cited by 436 publications

References 50 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

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