Istaroxime, a Stimulator of Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Isoform 2a Activity, as a Novel Therapeutic Approach to Heart Failure

Micheletti, R.; Palazzo, Fiorentina; Barassi, Paolo; Giacalone, Giuseppe; Ferrandi, Mara; Schiavone, Antonio; Moro, Barbara; Parodi, Oberdan; Ferrari, Paolo; Bianchi, Giuseppe

doi:10.1016/j.amjcard.2006.09.003

Cited by 60 publications

(52 citation statements)

References 31 publications

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“…Istaroxime (4 M) was acutely applied to myocytes from sham and AoB groups, and evaluation of functional parameters was performed as above. In sham myocytes, istaroxime effects were similar to those previously reported for normal guinea pig myocytes (Rocchetti et al, 2005;Micheletti et al, 2007). Istaroxime increased SR Ca 2ϩ content by 79.2 Ϯ 21.1% (p Ͻ 0.05 versus control; Fig.…”

Section: Resultssupporting

confidence: 86%

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

Alemanni²,

Mostacciuolo³

et al. 2008

J Pharmacol Exp Ther

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PST2744 [Istaroxime; (E,Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione hydrochloride)] is a novel inotropic agent that enhances sarco(endo)plasmic reticulum Ca 2ϩ ATPase (SERCA) 2 activity. We investigated the istaroxime effect on Ca 2ϩ handling abnormalities in myocardial hypertrophy/failure (HF). Guinea pig myocytes were studied 12 weeks after aortic banding (AoB) and compared with those of sham-operated animals (sham).

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Section: Resultssupporting

confidence: 86%

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

Alemanni²,

Mostacciuolo³

et al. 2008

J Pharmacol Exp Ther

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“…Others previously found preservation of intracellular ATP content and mitochondrial function by ranolazine during protection against ischemiareperfusion (20). Because ranolazine may impact other pathways, we also used istaroxime, a more specific SERCA activator (56). Thus, ranolazine and istaroxime may protect against chlorineinduced cardiotoxicity by protecting SERCA, thereby preserving mitochondrial and cellular functions.…”

Section: Discussionmentioning

confidence: 99%

Sarcoendoplasmic Reticulum Ca²⁺ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

Ahmad

Hendry‐Hofer

et al. 2015

Am J Respir Cell Mol Biol

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Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation-induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute highconcentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration-approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia-reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine-and istaroximetreated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure. Clinical RelevanceThis study defines impact of inhalation of a toxic gas, chlorine, on a critical cardiac calcium pump, sarcoendoplasmic reticulum Ca 21 ATPase (SERCA). It also demonstrates that therapeutic strategies that protect or modify SERCA function could be useful approaches for emergent resuscitation of severe chlorine inhalation victims.Chlorine is a commonly used chemical in industry and society. Acute chlorine inhalation toxicity can occur due to accidents at swimming pools and/or involving water purification systems, after transportation accidents, upon industrial exposure, with misuse of domestic cleaners, during military operations, and, more recently, through chemical terrorism. In the

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“…38,39 Due to its double action, istaroxime has been proved to treat acute HF syndrome in guinea pigs and dogs, improving systolic and diastolic function, central hemodynamics, systolic blood pressure, and reducing heart rate. [40][41][42] Istaroxime has also been used in human patients; the Hemodynamic, Echocardiographic, and Neurohor- …”

Section: Serca2a As a Therapeutic Target Pharmacological Therapiesmentioning

confidence: 99%

“…43 Istaroxime effect on SERCA2a is isoform specific since no effect of the drug was observed on SERCA1 from skeletal muscle. 40 Recently, the mechanism of istaroxime-driven SERCA2a activation has been addressed and it was observed that this effect is dependent on PLN presence. The SERCA2a/PLN complex was found to dissociate with increasing nanomolar istaroxime concentrations in a similar way to that observed with increasing Ca 2+ concentrations.…”

mentioning

confidence: 99%

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

Fragoso-Medina¹,

Zarain‐Herzberg²

2014

RRCC

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Abstract:The complexity of heart physiology has delayed the implementation of efficient, feasible, and safe therapies to fight against heart diseases for many years. As knowledge of the precise mechanisms governing cardiac hypertrophy and heart failure development increases, the availability of new therapeutic alternatives also grows. Since the cardiomyocyte physiology deeply depends on the correct calcium handling, many efforts to describe accurately the excitation-contraction coupling process in the heart and the proteins involved have been made. Among the proteins participating in calcium handling, sarco/endoplasmic reticulum Ca 2+ adenosine triphosphatase-2a (SERCA2a), whose expression and function is decreased in heart failure, stands out because of its critical role regulating Ca 2+ concentration in the cardiomyocyte. The importance of SERCA2a has been reflected in numerous studies aimed to describe its expression and function. Recently, gene therapy to deliver SERCA2a has shown promising results in human clinical trials. This paper reviews the current literature knowledge exploring diverse approaches to rescue SERCA2a expression in heart failure. It also discusses some data suggesting other possible therapies that could improve SERCA2a expression and function in cardiac diseases.

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Istaroxime, a Stimulator of Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Isoform 2a Activity, as a Novel Therapeutic Approach to Heart Failure

Cited by 60 publications

References 31 publications

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

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

Sarcoendoplasmic Reticulum Ca²⁺ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

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Istaroxime, a Stimulator of Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Isoform 2a Activity, as a Novel Therapeutic Approach to Heart Failure

Cited by 60 publications

References 31 publications

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

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

Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

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Sarcoendoplasmic Reticulum Ca²⁺ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity