Istaroxime stimulates SERCA2a and accelerates calcium cycling in heart failure by relieving phospholamban inhibition

Background and Purpose Calcium handling is known to be deranged in heart failure. Interventions aimed at improving cell Ca2+ cycling may represent a promising approach to heart failure therapy. Istaroxime is a new luso‐inotropic compound that stimulates cardiac contractility and relaxation in health...

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Bibliographic Details
Published in:British journal of pharmacology 2013-08, Vol.169 (8), p.1849-1861
Main Authors: Ferrandi, Mara, Barassi, Paolo, Tadini‐Buoninsegni, Francesco, Bartolommei, Gianluca, Molinari, Isabella, Tripodi, Maria Grazia, Reina, Cristina, Moncelli, Maria Rosa, Bianchi, Giuseppe, Ferrari, Patrizia
Format: Article
Language:English
Subjects:
Animals
Calcium
Calcium - metabolism
Calcium - pharmacokinetics
calcium uptake
Calcium-Binding Proteins - antagonists & inhibitors
charge measurements
Dogs
Etiocholanolone - analogs & derivatives
Etiocholanolone - pharmacology
Guinea Pigs
Heart failure
Heart Failure - drug therapy
Heart Failure - metabolism
Humans
In Vitro Techniques
inotropy
istaroxime
lusitropy
Male
Microsomes - metabolism
phospholamban
Rabbits
Research Papers
Rodents
Sarcoplasmic Reticulum - metabolism
sarcoplasmic reticulum Ca2+ ATPase
Sarcoplasmic Reticulum Calcium-Transporting ATPases - drug effects
Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases - pharmacokinetics
SERCA
Spodoptera
Spodoptera frugiperda
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Summary:Background and Purpose Calcium handling is known to be deranged in heart failure. Interventions aimed at improving cell Ca2+ cycling may represent a promising approach to heart failure therapy. Istaroxime is a new luso‐inotropic compound that stimulates cardiac contractility and relaxation in healthy and failing animal models and in patients with acute heart failure (AHF) syndrome. Istaroxime is a Na‐K ATPase inhibitor with the unique property of increasing sarcoplasmic reticulum (SR) SERCA2a activity as shown in heart microsomes from humans and guinea pigs. The present study addressed the molecular mechanism by which istaroxime increases SERCA2a activity. Experimental Approach To study the effect of istaroxime on SERCA2a‐phospholamban (PLB) complex, we applied different methodologies in native dog healthy and failing heart preparations and heterologous canine SERCA2a/PLB co‐expressed in Spodoptera frugiperda (Sf21) insect cells. Key Results We showed that istaroxime enhances SERCA2a activity, Ca2+ uptake and the Ca2+‐dependent charge movements into dog healthy and failing cardiac SR vesicles. Although not directly demonstrated, the most probable explanation of these activities is the displacement of PLB from SERCA2a.E2 conformation, independently from cAMP/PKA. We propose that this displacement may favour the SERCA2a conformational transition from E2 to E1, thus resulting in the acceleration of Ca2+ cycling. Conclusions and Implications Istaroxime represents the first example of a small molecule that exerts a luso‐inotropic effect in the failing human heart through the stimulation of SERCA2a ATPase activity and the enhancement of Ca2+ uptake into the SR by relieving the PLB inhibitory effect on SERCA2a in a cAMP/PKA independent way. Linked Articles This article is commented on by Huang, pp. 486–488 of volume 170 issue 3. To view this commentary visit http://dx.doi.org/10.1111/bph.12288.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.12278