Modulation of Sarcoplasmic Reticulum Function by PST2744 [Istaroxime; (E,Z)-3-((2-Aminoethoxy)imino) Androstane-6,17-dione Hydrochloride)] in a Pressure-Overload Heart Failure Model

Rocchetti, Marcella; Alemanni, Matteo; Mostacciuolo, Gaspare; Barassi, Paolo; Altomare, Claudia; Chisci, Riccardo; Micheletti, R.; Ferrari, Paolo; Zaza, Antonio

doi:10.1124/jpet.108.138701

Cited by 34 publications

(23 citation statements)

References 37 publications

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“…Istaroxime, (E, Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione hydrochloride) enhances SR Ca 2+ content and Ca 2+ uptake in failing cardiomyocytes and improves heart function in a guinea pig aortic binding model56, 57. This finding opens new perspective for the pharmacotherapy of HF.…”

Section: Small Molecules Targeting Serca Activitymentioning

confidence: 81%

Sarcoplasmic reticulum Ca²⁺ATPase as a therapeutic target for heart failure

Lipskaia

Chemaly

Hadri

et al. 2009

Expert Opinion on Biological Therapy

160

130

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Background-The cardiac isoform of the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA2a) plays a major role in controlling excitation/contraction coupling. In both experimental and clinical heart failure (HF), SERCA2a expression is significantly reduced which leads to abnormal Ca 2+ handling and deficient contractility. A large number of studies in isolated cardiac myocytes, in small and large animal models of HF showed that restoring SERCA2a expression by gene transfer corrects the contractile abnormalities and improves energetics and electrical remodeling. Following a long line of investigation, a clinical trial is underway to restore SERCA2a expression in patients with HF using adeno-associated virus type 1.

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Section: Small Molecules Targeting Serca Activitymentioning

confidence: 81%

Sarcoplasmic reticulum Ca²⁺ATPase as a therapeutic target for heart failure

Lipskaia

Chemaly

Hadri

et al. 2009

Expert Opinion on Biological Therapy

160

130

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“…Of these, pharmacological phosphodiesterase inhibition to increase cAMP availability and hence SERCA activity has been translated from the laboratory setting to clinical trial stages, only to be withdrawn because of an increased incidence of sudden death. 18 In a similar vein, pharmacological stimulation of SERCA with the Na/K ATPase antagonist istaroxime [19][20][21] has also been pursued in heart failure. However, once again, after initial promise in experimental studies and early clinical trials, substantive clinical trials were suspended.…”

Section: Restoration Of Serca As a Therapeutic Strategymentioning

confidence: 99%

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Eisner

Caldwell

Trafford

2013

Circulation Research

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T his article reflects on the impact of a classic paper identifying the effects of loss of sarcoplasmic reticulum Ca-ATPase activity in heart failure. The Classic ArticleUnderstanding the effects of heart failure on contraction and Ca signaling in the heart has long been a priority. By the late 1980s, many studies on animal models had shown that heart failure resulted in a slowing of the decay of the systolic Ca transient 1 because of a decrease in the expression of the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA).2 Work using human tissue found similar changes.3,4 In 1994, Hasenfuss et al 5 published a now classic article in Circulation Research entitled "Relation between myocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and non-failing human myocardium." Previous work had shown that SERCA expression and activity were decreased in heart failure. Other work had shown that the increase of force seen on increasing the frequency of stimulation (the positive forcefrequency curve) disappeared in heart failure. Hasenfuss et al 5 showed that the degree of change in the force-frequency relationship correlated with the loss of SERCA. Hearts with low levels of SERCA developed maximum force at lower frequencies than those with higher levels. In addition, and suggested as causative of the reduced force-frequency responses, the failing hearts had reduced SERCA-mediated Ca uptake.The work in this article has influenced 2 areas of research: changes of SR function in heart failure and restoration of SERCA as a therapeutic strategy. We consider these in turn. SR Function in Heart FailureTwenty years later, the role of changes of SERCA expression in heart failure is well-established. The majority of studies of heart failure in either humans or experimental animals show that SERCA activity is decreased in heart failure. This decrease of SERCA has 2 immediate effects on Ca signaling. First, it slows the rate of decay of the systolic Ca transient, thereby impairing relaxation. Second, as a consequence of decreasing SR Ca content, it will decrease the amplitude of the systolic Ca transient and thus contraction. However, subsequent work has shown that changes of SERCA are part of a group of changes of Ca signaling that occur in heart failure. As highlighted in Figure, 2 other factors will also decrease the SR Ca content. First, there is an increase of NCX expression or activity. [6][7][8] This adaptation has the benefit of making up for the reduced SERCA, thereby preserving relaxation. In a subsequent article, Hasenfuss et al 9 showed that patients with increased NCX had better diastolic function than did those with lower NCX. However, although increased NCX improves diastolic function, it will decrease SR Ca content and thereby depress systolic function further. Second, many studies have now shown that the open probability of the RyR is increased in heart failure. [10][11][12] This may occur as a result of phosphorylation, 10 hyponitrosylation, 13 or oxidation. 14 This increased opening will lead to a...

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“…1A). This model further validated the strategies of decreasing PLB expression and increasing PLB phosphorylation, and it motivated the search for a drug that uncouples PLB from SERCA2a (Cornea et al 2013; Ferrandi et al 2013; Huang 2013; Khan et al 2009; Rocchetti et al 2008). Recent electron paramagnetic resonance (EPR) (James et al 2012), nuclear magnetic resonance (NMR) (Gustavsson et al 2013), and fluorescence resonance energy transfer (FRET) (Dong and Thomas 2014) studies have revealed that PLB is essentially a subunit of SERCA2a, remaining tightly bound even after phosphorylation (Fig.…”

Section: Introductionmentioning

confidence: 72%

“…Istaroxime (Ferrandi et al 2013; Huang 2013; Khan et al 2009; Rocchetti et al 2008), which increases diastolic function in humans (Khan et al 2009), has been shown to partially decouple SERCA2a and phospholamban. Istaroxime altered V max and pK Ca of SERCA2a only in the presence of PLB, so its regulation of SERCA2a must result from its interaction with PLB (Ferrandi et al 2013).…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

“…Unphosphorylated PLB (U-PLB) inhibits SERCA2a, but phosphorylation at S16 and/or T17 (producing P-PLB) changes the structure of PLB to relieve SERCA2a inhibition. Because insufficient SERCA2a activity is a hallmark of heart failure, SERCA2a activation (by gene therapy (Andino et al 2008; Fish et al 2013; Hoshijima et al 2002; Jessup et al 2011) or drug therapy (Ferrandi et al 2013; Huang 2013; Khan et al 2009; Rocchetti et al 2008; Zhang et al 2012)) is a widely sought goal for treatment of heart failure. This review describes rational approaches to this goal.…”

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confidence: 99%

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Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

Ablorh

Thomas

2015

Biophys Rev

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We review the recent development of novel biochemical and spectroscopic methods to determine the site-specific phosphorylation, expression, mutation, and structural dynamics of phospholamban (PLB), in relation to its function (inhibition of the cardiac calcium pump, SERCA2a), with specific focus on cardiac physiology, pathology, and therapy. In the cardiomyocyte, SERCA2a actively transports Ca2+ into the sarcoplasmic reticulum (SR) during relaxation (diastole) to create the concentration gradient that drives the passive efflux of Ca2+ required for cardiac contraction (systole). Unphosphorylated PLB (U-PLB) inhibits SERCA2a, but phosphorylation at S16 and/or T17 (producing P-PLB) changes the structure of PLB to relieve SERCA2a inhibition. Because insufficient SERCA2a activity is a hallmark of heart failure, SERCA2a activation (by gene therapy (Andino et al. 2008; Fish et al. 2013; Hoshijima et al. 2002; Jessup et al. 2011) or drug therapy (Ferrandi et al. 2013; Huang 2013; Khan et al. 2009; Rocchetti et al. 2008; Zhang et al. 2012)) is a widely sought goal for treatment of heart failure. This review describes rational approaches to this goal. Novel biophysical assays, using site-directed labeling and high-resolution spectroscopy, have been developed to resolve the structural states of SERCA2a-PLB complexes in vitro and in living cells. Novel biochemical assays, using synthetic standards and multidimensional immunofluorescence, have been developed to quantitate PLB expression and phosphorylation states in cells and human tissues. The biochemical and biophysical properties of U-PLB, P-PLB, and mutant PLB will ultimately resolve the mechanisms of loss of inhibition and gain of inhibition to guide therapeutic development. These assays will be powerful tools for investigating human tissue samples from the Sydney Heart Bank, for the purpose of analyzing and diagnosing specific disorders.

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Modulation of Sarcoplasmic Reticulum Function by PST2744 [Istaroxime; (E,Z)-3-((2-Aminoethoxy)imino) Androstane-6,17-dione Hydrochloride)] in a Pressure-Overload Heart Failure Model

Cited by 34 publications

References 37 publications

Sarcoplasmic reticulum Ca²⁺ATPase as a therapeutic target for heart failure

Sarcoplasmic reticulum Ca²⁺ATPase as a therapeutic target for heart failure

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

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Modulation of Sarcoplasmic Reticulum Function by PST2744 [Istaroxime; (E,Z)-3-((2-Aminoethoxy)imino) Androstane-6,17-dione Hydrochloride)] in a Pressure-Overload Heart Failure Model

Cited by 34 publications

References 37 publications

Sarcoplasmic reticulum Ca2+ATPase as a therapeutic target for heart failure

Sarcoplasmic reticulum Ca2+ATPase as a therapeutic target for heart failure

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

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Product

Resources

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Sarcoplasmic reticulum Ca²⁺ATPase as a therapeutic target for heart failure

Sarcoplasmic reticulum Ca²⁺ATPase as a therapeutic target for heart failure