SR Ca(2+)-ATPase activity and expression in ventricular myocardium of dogs with heart failure

Gupta, Ramesh C.; Shimoyama, Hisashi; Tanimura, Mitsuhiro; Nair, Rajiv; Lesch, Michael; Sabbah, Hani N.

doi:10.1152/ajpheart.1997.273.1.h12

Cited by 37 publications

(29 citation statements)

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“…43 Interestingly, interventricular differences in RyR2 expression were eliminated, and total RyR2 expression decreased in dogs with arrhythmogenic right ventricular cardiomyopathy. 41 Similarly, Gupta et al 44 found reduced SERCA2a activity and protein levels in LV, but not RV, in dogs with chronic heart failure, eliminating interventricular differences. These data suggest that interventricular differences in Ca 2+ handling are species dependent and can be further regulated by chamber-specific disease-related remodeling.…”

Section: Differences In Ca 2+ Handling and Contractilitymentioning

confidence: 92%

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

Molina

Heijman

Dobrev

2016

Arrhythmia &Amp; Electrophysiology Review

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Optimal cardiac function depends on appropriate rate and force of contraction, with specific cardiac regions having developed particular beat-to-beat properties depending on their individual functions. For example, isovolumetric contraction time is shorter in the right ventricle (RV) than in the left ventricle (LV). At the cellular level, cardiac function is regulated by regional cardiomyocyte electrophysiological and Ca 2+ -handling properties (see Figure 1). Differences in these properties between nodal cells and working myocardium, 1,2 atrial and ventricular cardiomyocytes 1,3,4 and different layers of the LV wall (endo-, mid-and epicardium) [5][6][7] have been well established. Although electrophysiological differences between left and right sides of the heart have been less extensively characterised there is evidence for clinically relevant left-toright differences in the atrium 1,[8][9][10] and the ventricle. 1,5,[11][12][13][14] Here, we review the known differences in LV and RV electrophysiology and Ca 2+ handling at baseline and during pathophysiological conditions. Furthermore, we discuss the implications of these differences for arrhythmogenesis. Basic Cardiac Electrophysiology and Arrhythmia MechanismsCardiac excitation-contraction (EC) coupling is a sequence of events occurring in cardiomyocytes upon electrical activation, resulting in the generation of an action potential (AP) and subsequent cardiomyocyte contraction (see Figure 2). This sequence shows many similarities between different cell types, notably between LV and RV cardiomyocytes.In this section we briefly summarise the common features. Figure 2A). Moreover, the Ca 2+ entering the cardiomyocyte through L-type Ca 2+ channels plays a critical role initiating EC coupling by activating type-2 ryanodine receptor (RyR2) channels on the sarcoplasmic reticulum (SR) membrane, producing a much larger SR Ca 2+ release. This process is termed Ca 2+ -induced Ca 2+ release (CICR) and results in an increase in the cytoplasmic Ca 2+ concentration sufficient to activate the contractile apparatus, initiating cardiomyocyte contraction. 15 Subsequently, resequestration of Ca 2+ in the SR by the SR Ca 2+ ATPase type-2a (SERCA2a) and extrusion of Ca 2+ to the extracellular space by the Na + -Ca 2+ exchanger type-1 (NCX1) returns cytosolic Ca 2+ to diastolic levels, promoting cellular relaxation. Finally, ionic homeostasis of intracellular Na + and K + is maintained by the Na + / Abstract A wide range of ion channels, transporters, signaling pathways and tissue structure at a microscopic and macroscopic scale regulate the electrophysiological activity of the heart. Each region of the heart has optimised these properties based on its specific role during the cardiac cycle, leading to well-established differences in electrophysiology, Ca 2+ handling and tissue structure between atria and ventricles and between different layers of the ventricular wall. Similarly, the right ventricle (RV) and left ventricle (LV) have different embryological, structural, metabol...

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Section: Differences In Ca 2+ Handling and Contractilitymentioning

confidence: 92%

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

Molina

Heijman

Dobrev

2016

Arrhythmia &Amp; Electrophysiology Review

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“…17 For thapsigargin-sensitive SERCA2a activity measurements, membrane vesicles were prepared from LV tissue as previously described. 18 SERCA2a activity was determined in the absence and presence of thapsigargin at varying calcium concentration (0.1 to 10.0 mol/L) as previously described 18 and the activity expressed as mol Pi released/min per mg of noncollagen protein.…”

Section: Determination Of Sr Camentioning

confidence: 99%

Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment

Sabbah¹,

Sharov²,

Gupta³

et al. 2003

Circulation Research

102

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Abstract-Passive mechanical containment of failing left ventricle (LV) with the Acorn Cardiac Support Device (CSD) was shown to prevent progressive LV dilation in dogs with heart failure (HF) and increase ejection fraction. To examine possible mechanisms for improved LV function with the CSD, we examined the effect of CSD therapy on the expression of cardiac stretch response proteins, myocyte hypertrophy, sarcoplasmic reticulum Ca 2ϩ -ATPase activity and uptake, and mRNA gene expression for myosin heavy chain (MHC) isoforms. HF was produced in 12 dogs by intracoronary microembolization. Six dogs were implanted with the CSD and 6 served as concurrent controls. LV tissue from 6 normal dogs was used for comparison. Compared with normal dogs, untreated HF dogs showed reduced cardiomyocyte contraction and relaxation, upregulation of stretch response proteins (p21ras, c-fos, and p38 ␣/␤ mitogen-activated protein kinase), increased myocyte hypertrophy, reduced SERCA2a activity with unchanged affinity for calcium, reduced proportion of mRNA gene expression for ␣-MHC, and increased proportion of ␤-MHC. Therapy with the CSD was associated with improved cardiomyocyte contraction and relaxation, downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, increased affinity of the pump for calcium, and restoration of ␣-and ␤-MHC isoforms ratio. The results suggest that preventing LV dilation and stretch with the CSD promotes downregulation of stretch response proteins, attenuates myocyte hypertrophy and improves SR calcium cycling. These data offer possible mechanisms for improvement of LV function after CSD therapy. Key Words: heart failure Ⅲ myocyte hypertrophy Ⅲ sarcoplasmic reticulum Ⅲ myosin heavy chain H eart failure (HF) is a progressive disorder mediated through multiple signaling pathways. Once initiated, HF is characterized by increased neurohumoral activation and ventricular dilation. Although such compensatory changes are initially beneficial, over the long-term they cause adverse structural and functional changes collectively referred to as ventricular remodeling. Ventricular dilation also causes increased mechanical stress and myocardial stretch. Upregulation of stretch response proteins, such as p21ras, 1 c-fos, 2,3 and p38 ␣/␤ mitogen-activated protein kinase (MAPK), 4 have been shown to induce cardiomyocyte hypertrophy.The Acorn Cardiac Support Device (CSD) has been shown to halt progressive left ventricular (LV) dilation and improve ejection fraction. [5][6][7] However, the mechanism(s) underlying the improved cardiac function has not been elucidated. In the present study, we tested the hypothesis that improvement in LV systolic function in dogs with HF after long-term therapy with the CSD results, in part, from downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, 1-4 and improvement of sarcoplasmic reticulum (SR) calcium cycling. To further understand the mechanisms for the improvement in LV systolic function, we also explored the influence of ...

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“…In recent years there has been a great deal of attention paid to intracellular mediators of hypertrophic signaling cascades, and data have been inferred to link some of these proteins and transcription factors to the early development of heart failure. [2][3][4][5][6] To that end, many protein kinases and their substrates that mediate the expression of hypertrophy and progression to heart failure have been relatively well characterized. Much less relative attention has been paid to the protein phosphatases in this regard.…”

mentioning

confidence: 99%

“…[1][2][3][4] This slower decline has been attributed to a decrease in the Ca 2ϩ uptake into the sarcoplasmic reticulum (SR); and particularly with the relative role of phospholamban (PLB) and the SR Ca 2ϩ -ATPase (SERCA). 4,5 Whereas previous work has successfully targeted PLB and SERCA in the investigational treatment of heart failure in mouse, rat, and human myocytes, more recent work has focused on the potential modulators of this system to elucidate the pathophysiologic changes that result in aberrant calcium handling. [2][3][4][5][6] In this issue, Pathak and del Monte et al show that targeted inhibition of protein phosphatase 1 (PP1) by increased activity of its inhibitor, inhibitor-1 in the heart, results in enhanced contractility and is protective against the development of cardiac hypertrophy and heart failure stimulated by hemodynamic load.…”

mentioning

confidence: 99%

“…4,5 Whereas previous work has successfully targeted PLB and SERCA in the investigational treatment of heart failure in mouse, rat, and human myocytes, more recent work has focused on the potential modulators of this system to elucidate the pathophysiologic changes that result in aberrant calcium handling. [2][3][4][5][6] In this issue, Pathak and del Monte et al show that targeted inhibition of protein phosphatase 1 (PP1) by increased activity of its inhibitor, inhibitor-1 in the heart, results in enhanced contractility and is protective against the development of cardiac hypertrophy and heart failure stimulated by hemodynamic load. 7 In failing hearts, the downregulation of adrenergic receptor and cAMP-dependent protein kinase signaling leads to the inactivation of inhibitor-1 which, in turn, results in increased activity of PP1.…”

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confidence: 99%

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Targeting Protein Phosphatase 1 in Heart Failure

Champion

2005

Circulation Research

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O ver the past three decades the treatment of heart failure has shifted from a palliative care approach to a more successful focus on neurohormonal modulation through drugs that inhibit ␤-adrenergic, angiotensin, and aldosterone signaling. Despite these relatively recent advances, the clinical syndrome of heart failure remains progressive in nature. This observation begs the question as to a unifying aberrancy in cardiomyocyte phenotype that occurs in heart failure. More recently great attention has been paid to the alterations in calcium handling and has typically been associated with calcium-transients that are of a lower amplitude and slower decline than normal cardiomyocytes. [1][2][3][4] This slower decline has been attributed to a decrease in the Ca 2ϩ uptake into the sarcoplasmic reticulum (SR); and particularly with the relative role of phospholamban (PLB) and the SR Ca 2ϩ -ATPase (SERCA). 4,5 Whereas previous work has successfully targeted PLB and SERCA in the investigational treatment of heart failure in mouse, rat, and human myocytes, more recent work has focused on the potential modulators of this system to elucidate the pathophysiologic changes that result in aberrant calcium handling. [2][3][4][5][6] In this issue, Pathak and del Monte et al show that targeted inhibition of protein phosphatase 1 (PP1) by increased activity of its inhibitor, inhibitor-1 in the heart, results in enhanced contractility and is protective against the development of cardiac hypertrophy and heart failure stimulated by hemodynamic load. 7 In failing hearts, the downregulation of adrenergic receptor and cAMP-dependent protein kinase signaling leads to the inactivation of inhibitor-1 which, in turn, results in increased activity of PP1. 7,8 This activation of PP1 leads to the dephosphorylation of phospholamban thus reducing calcium uptake by SERCA-2a. In an important series of experiments in transgenic mice and using gene transfer in rats, Kranias, Hajjar, and colleagues now show that the targeted inhibition of protein phosphatase 1 by overexpression of inhibitor-1 enhances cardiac contractility under normal hemodynamic conditions as well as in response to adrenergic stimulation with isoproterenol. Moreover, the authors show that targeted gene transfer of active inhibitor-1 in rats results in marked attenuation of the functional and morphometric changes associated with chronic pressure overload.As a first step, the investigators determined the influence of the expression of a constitutively active, truncated analog of inhibitor-1 that was targeted to the cardiac myocytes. Both intact hearts and isolated myocytes expressing this activated inhibitor-1 exhibited enhanced contractility under basal conditions and augmented responsiveness to adrenergic stimulation. This enhanced contractility was associated with increased phosphorylation of phospholamban and the subsequent enhanced SERCA-2a activity.When subjected to chronic pressure overload, mice expressing active inhibitor-1 exhibited less cardiac hypertrophy and interstitial f...

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SR Ca(2+)-ATPase activity and expression in ventricular myocardium of dogs with heart failure

Cited by 37 publications

References 0 publications

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment

Targeting Protein Phosphatase 1 in Heart Failure

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