Effect of ablation of phospholamban on dynamics of cardiac myocyte contraction and intracellular Ca2+

Wolska, Beata M.; Stojanovic, Miroslav O.; Luo, Wusheng; Kranias, Evangelia G.; Solaro, R. John

doi:10.1152/ajpcell.1996.271.1.c391

Cited by 148 publications

(69 citation statements)

References 16 publications

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“…The lack of alteration of the isoproterenol response by thapsigargin, which essentially removes the SR contribution to contraction, would support this contention. In Plb-KO mice the response of the myocytes to isoproterenol has been reported as decreased (35), but the difference from the present study is that, in the Plb-KO myocytes, isoproterenol is acting on a background of raised basal contraction. The maximum amplitude attained after isoproterenol treatment, however, is similar in cells from wild-type and Plb-KO mice, probably because of a intrinsic limitation in the maximum contraction of an individual myocyte.…”

Section: Discussioncontrasting

confidence: 97%

Interaction between increased SERCA2a activity and β-adrenoceptor stimulation in adult rabbit myocytes

Chaudhri

Monte

Hajjar

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Chaudhri, Babar, Federica del Monte, Roger J. Hajjar, and Sian E. Harding. Interaction between increased SERCA2a activity and ␤-adrenoceptor stimulation in adult rabbit myocytes. Am J Physiol Heart Circ Physiol 283: H2450-H2457, 2002. First published August 8, 2002 10.1152 10. /ajpheart.00391.2002plasmic reticulum Ca 2ϩ -ATPase (SERCA)2a overexpression and phospholamban depletion have been shown to have beneficial effects on contractility in heart failure. However, the high sympathetic tone during development of failure may interact with increases in SERCA2a activity in potentially deleterious ways. We used adenoviral vectors to overexpress SERCA2a or partially downregulate phospholamban in adult rabbit ventricular myocytes in culture and studied the responses of these cells to ␤-adrenoceptor stimulation. SERCA2a overexpression and phospholamban depletion had quantitatively similar effects on basal contraction amplitude and in accelerating relaxation. Increasing SERCA2a activity by either strategy had little effect on the increase in contraction amplitude or incidence of arrhythmias with increasing isoproterenol. Maximum acceleration of relaxation by ␤-adrenoceptor stimulation was similar to that produced by SERCA2a overexpression. Isoproterenol treatment of SERCA2a-overexpressing or phospholamban-deficient myocytes produced a further modest decrease in relaxation time, with similar final values in both groups. We find no evidence for Ca 2ϩ overload induced by SERCA2a overexpression alone or in combination with catecholamines. phospholamban; antisense; aftercontraction; arrhythmia THERE IS ACCUMULATING EVIDENCE that stimulation of Ca 2ϩ uptake into the sarcoplasmic reticulum (SR), either by overexpression of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2a or by downregulation of the inhibitory protein phospholamban, is a promising strategy for support of the failing heart. Transgenic mice overexpressing SERCA2a were more resistant to induction of heart failure by aortic banding or diabetes than wild-type mice (15, 31). Similarly, phospholamban knockout (Plb-KO) mice have no increased mortality and can rescue various transgenic heart failure phenotypes (11,20,21,29). Transfection of myocytes from the failing human heart with adenoviral vectors for either SERCA2a or antisense message for phospholamban enhances contractile function, reversing the slowing of relaxation and depression of the frequencyresponse curve that are hallmarks of the failing heart (6, 8). Similarly, rescue of contractile function was seen in rats approaching senescence or with heart failure secondary to aortic banding (22,26). Expected problems related to SR overload resulting from these interventions have not materialized. Instead, the arrhythmogenic potential of increased extracellular Ca 2ϩ was reduced after SERCA2a overexpression in rabbit myocytes and cell viability was increased (4). In vivo transfections showed reduced mortality in the rat model of heart failure, with a decrease in incidence of arrhythmias and improved maintenanc...

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Section: Discussioncontrasting

confidence: 97%

Interaction between increased SERCA2a activity and β-adrenoceptor stimulation in adult rabbit myocytes

Chaudhri

Monte

Hajjar

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…PLB −/− myocytes showed the typical enhanced basal contractility, and thus exhibited reduced β-adrenergic responsiveness upon perfusion with 0.01 μmol/L ISO compared to WT myocytes, as has been previously demonstrated [27]. However, superfusion with 0.01 μmol/L ISO+10 μmol/L SIN-1 had no effect on the [Ca 2+ ] i transient amplitude or on myocyte shortening (n = 22 myocytes/6 hearts; [Ca 2+ ] i Transient: 23±4% vs.20±7%, Shortening: 62±20% vs. 64±21% Δ from CONT).…”

Section: Effect Of Sin-1 On Plb −/− Myocyte Functionsupporting

confidence: 79%

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high SIN-1 (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, while the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz and [Ca 2+ ] i transients and shortening were recorded. Following submaximal ISO (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, while cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. 10 μmol/L SIN-1 also increased basal contractility. Interestingly, SIN-1 only produced a contractile effect under one condition in phospholamban knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

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“…Interestingly, the absence of cardiac pathology in the phospholamban knockout mouse, which also exhibits elevated intracellular [Ca 2ϩ ] i via enhancements in SR Ca 2ϩ uptake, 31 suggests that the source of the Ca 2ϩ imbalance (I Ca,L versus SERCA2a:phospholamban ratio) might be an important factor in disease initiation. The subsarcolemmal colocalization of calcineurin 32 and PKC with the L-type Ca 2ϩ channel via the A-kinase anchoring protein AKAP79 33 supports the notion that these molecules may respond preferentially to local elevations in submembrane Ca 2ϩ , as expected after enhancements in I Ca,L versus bulk cytosolic Ca 2ϩ .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Calcineurin and Sarcolemmal Ca ²⁺ Influx Protects Cardiac Morphology and Ventricular Function in K _v 4.2N Transgenic Mice

et al. 2002

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Background-Cardiac-targeted expression of truncated K v 4.2 subunit (K v 4.2N) reduces transient outward current (I to ) density, prolongs action potentials (APs), and enhances contractility in 3-to 4-week-old transgenic mice. By 13 to 15 weeks of age, these mice develop severely impaired cardiac function and signs of heart failure. In this study, we examined whether augmented contractility in K v 4.2N mice results from elevations in intracellular calcium ([Ca 2ϩ ] i ) secondary to AP prolongation and investigated the putative roles of calcineurin activation in heart disease development of K v 4.2N mice. Methods and Results-At 3 to 4 weeks of age, L-type Ca 2ϩ influx and peak [Ca 2ϩ ] i were significantly elevated in K v 4.2N myocytes compared with control because of AP prolongation. Cardiac calcineurin activity was also significantly elevated in K v 4.2N mice by 5 weeks of age relative to controls and increased progressively as heart disease developed. This was associated with activation of protein kinase C (PKC)-␣ and PKC-but not PKC-⑀, as well as increases in ␤-myosin heavy chain (␤-MHC) and reductions in sarcoplasmic/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA)-2a expression. Treatment with either cyclosporin A or verapamil prevented increases in heart weight to body weight ratios, interstitial fibrosis, impaired contractility, PKC activation, and changes in the expression patterns of ␤-MHC and SERCA2a.Conclusions-Our results demonstrate that AP prolongation caused by I to reduction results in enhanced Ca 2ϩ cycling and hypercontractility in mice and suggests that elevations in [Ca 2ϩ ] i via I Ca,L and activation of calcineurin play a central role in disease development after I to reduction using the K v 4

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Effect of ablation of phospholamban on dynamics of cardiac myocyte contraction and intracellular Ca2+

Cited by 148 publications

References 16 publications

Interaction between increased SERCA2a activity and β-adrenoceptor stimulation in adult rabbit myocytes

Interaction between increased SERCA2a activity and β-adrenoceptor stimulation in adult rabbit myocytes

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Inhibition of Calcineurin and Sarcolemmal Ca ²⁺ Influx Protects Cardiac Morphology and Ventricular Function in K _v 4.2N Transgenic Mice

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Effect of ablation of phospholamban on dynamics of cardiac myocyte contraction and intracellular Ca2+

Cited by 148 publications

References 16 publications

Interaction between increased SERCA2a activity and β-adrenoceptor stimulation in adult rabbit myocytes

Interaction between increased SERCA2a activity and β-adrenoceptor stimulation in adult rabbit myocytes

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Inhibition of Calcineurin and Sarcolemmal Ca 2+ Influx Protects Cardiac Morphology and Ventricular Function in K v 4.2N Transgenic Mice

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Inhibition of Calcineurin and Sarcolemmal Ca ²⁺ Influx Protects Cardiac Morphology and Ventricular Function in K _v 4.2N Transgenic Mice