title: Istaroxime stimulates SERCA2a and accelerates calcium cycling in heart failure by relieving phospholamban inhibition.
abstract: OBJECTIVE
  Calcium handling is known to be deranged in heart failure. Interventions aimed at improving cell Ca(2) (+) 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  We showed that istaroxime enhances SERCA2a activity, Ca(2) (+) uptake and the Ca(2) (+) -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 Ca(2) (+) cycling.
  
  
  CONCLUSIONS
  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 Ca(2) (+) uptake into the SR by relieving the PLB inhibitory effect on SERCA2a in a cAMP/PKA independent way.
authors.affiliation: Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Ferrandi
authors.forename: Paolo
authors.initials: P
authors.lastname: Barassi
authors.forename: Francesco
authors.initials: F
authors.lastname: Tadini-Buoninsegni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolommei
authors.forename: Isabella
authors.initials: I
authors.lastname: Molinari
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tripodi
authors.forename: Cristina
authors.initials: C
authors.lastname: Reina
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Moncelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008861:Microsomes / Q000378:metabolism; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism / Q000493:pharmacokinetics*; D018411:Spodoptera; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D005043:Etiocholanolone; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C468128:Istaroxime
keywords: SERCA; calcium uptake; charge measurements; heart failure; inotropy; istaroxime; lusitropy; phospholamban; sarcoplasmic reticulum Ca2+ ATPase