title: Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats.
abstract: OBJECTIVE
  Estrogens enhance ischemia tolerance (IT) in the myocardium, the mechanism of which remains unclear. We investigated the effects of long-term estrogen deprivation on the intracellular calcium (Ca(2+)(i)) transient of the heart and its possible influence on IT.
  
  
  METHODS
  Hearts of ovariectomized (OVX) and sham-operated (control) adult female rats (some receiving estrogen therapy) were studied 10 weeks after surgical operation: control (n = 8), OVX (n = 10), sham-operated estrogen-substituted (n = 7), and ovariectomized estrogen-substituted (n = 9). In vivo heart function was assessed by echocardiography, whereas Ca(2+)(i) transients were recorded, concomitantly with left ventricular pressure and coronary flow, by Indo-1 surface fluorometry in isolated Langendorff-perfused hearts. Isolated hearts were subjected to a 30-minute global ischemia-30-minute reperfusion protocol. Left ventricular expression of myocardial sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), and Ser16-phosphorylated PLB was measured.
  
  
  RESULTS
  Ovariectomy did not influence resting cardiac function in vivo or ex vivo. However, Ca(2+) removal was slower. During ischemia, Ca(2+)(i) elevation and ischemic contracture were more pronounced after ovariectomy. Postischemic restitution of inotropic function (developed pressure; +dP/dt(max)) and lusitropic function (-dP/dt(max)) and Ca(2+)(i) transient recovery (amplitude; ±dCa(2+)(i)/dt(max)) were decreased in OVX hearts. Sarcoendoplasmic reticulum Ca(2+)-ATPase expression was unaltered, whereas PLB and Ser16-phosphorylated PLB levels were higher after ovariectomy. All effects of ovariectomy were restored by estrogen therapy.
  
  
  CONCLUSIONS
  Ovariectomy impairs myocardial Ca(2+) removal by increasing the expression of the SERCA2a inhibitor PLB. Defective Ca(2+) transport causes ischemic Ca(2+)(i) overload and insufficient postischemic recovery of Ca(2+)(i) transients, which entail depressed hemodynamic restitution. Protection of intact Ca(2+) cycling in the myocardium by estrogens plays a major role in enhancing IT.
authors.affiliation: From the 1Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary; and 2Second Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor Artúr
authors.initials: GA
authors.lastname: Dunay
authors.forename: Péter
authors.initials: P
authors.lastname: Paragi
authors.forename: Levente
authors.initials: L
authors.lastname: Sára
authors.forename: Nándor
authors.initials: N
authors.lastname: Ács
authors.forename: Bernadett
authors.initials: B
authors.lastname: Balázs
authors.forename: Viktor
authors.initials: V
authors.lastname: Ágoston
authors.forename: Csaba
authors.initials: C
authors.lastname: Répás
authors.forename: Tamás
authors.initials: T
authors.lastname: Ivanics
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Miklós
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006321:Heart / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000378:metabolism*; D010052:Ovariectomy / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D004967:Estrogens; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban