Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats

Gábor Artúr Dunay, Péter Paragi, Levente Sára, Nándor Ács, Bernadett Balázs, Viktor Ágoston, Csaba Répás, Tamás Ivanics, Zsuzsanna Miklós

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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 (Ca2+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 Ca2+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 Ca2+-ATPase (SERCA2a), phospholamban (PLB), and Ser16-phosphorylated PLB was measured. Results: Ovariectomy did not influence resting cardiac function in vivo or ex vivo. However, Ca2+ removal was slower. During ischemia, Ca2+i elevation and ischemic contracture were more pronounced after ovariectomy. Postischemic restitution of inotropic function (developed pressure; +dP/dtmax) and lusitropic function (-dP/dtmax) and Ca2+i transient recovery (amplitude; ±dCa2+i/dtmax) were decreased in OVX hearts. Sarcoendoplasmic reticulum Ca2+-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 Ca2+ removal by increasing the expression of the SERCA2a inhibitor PLB. Defective Ca2+ transport causes ischemic Ca2+i overload and insufficient postischemic recovery of Ca2+i transients, which entail depressed hemodynamic restitution. Protection of intact Ca2+ cycling in the myocardium by estrogens plays a major role in enhancing IT.

Original languageEnglish
Pages (from-to)773-782
Number of pages10
Issue number7
Publication statusPublished - Jul 8 2015


  • Ca transients
  • Cardiac ischemia tolerance
  • Estrogen deficiency
  • Indo-1 fluorometry
  • Isolated heart
  • Sarcoendoplasmic reticulum Ca-ATPase

ASJC Scopus subject areas

  • Obstetrics and Gynaecology

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    Dunay, G. A., Paragi, P., Sára, L., Ács, N., Balázs, B., Ágoston, V., Répás, C., Ivanics, T., & Miklós, Z. (2015). Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats. Menopause, 22(7), 773-782.