钙循环抑制导致雌激素缺乏大鼠心脏的缺血耐受性降低。
Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats.
作者信息
Dunay Gábor Artúr, Paragi Péter, Sára Levente, Ács Nándor, Balázs Bernadett, Ágoston Viktor, Répás Csaba, Ivanics Tamás, Miklós Zsuzsanna
机构信息
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.
出版信息
Menopause. 2015 Jul;22(7):773-82. doi: 10.1097/GME.0000000000000377.
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.
目的
雌激素可增强心肌的缺血耐受性（IT），但其机制尚不清楚。我们研究了长期雌激素缺乏对心脏细胞内钙（Ca(2+)(i)）瞬变的影响及其对IT的可能影响。
方法
在手术10周后研究去卵巢（OVX）和假手术（对照）成年雌性大鼠（部分接受雌激素治疗）的心脏：对照组（n = 8）、OVX组（n = 10）、假手术雌激素替代组（n = 7）和去卵巢雌激素替代组（n = 9）。通过超声心动图评估体内心脏功能，而在离体Langendorff灌注心脏中，通过Indo-1表面荧光法记录Ca(2+)(i)瞬变，同时记录左心室压力和冠状动脉血流量。将离体心脏进行30分钟全心缺血-30分钟再灌注方案。测量心肌肌浆网Ca(2+)-ATP酶（SERCA2a）、受磷蛋白（PLB）和Ser16磷酸化PLB在左心室的表达。
结果
卵巢切除术对体内或体外静息心脏功能无影响。然而，Ca(2+)清除较慢。在缺血期间，卵巢切除术后Ca(2+)(i)升高和缺血性挛缩更明显。OVX心脏中缺血后变力功能（发展压力；+dP/dt(max)）和舒张功能（-dP/dt(max)）的恢复以及Ca(2+)(i)瞬变恢复（幅度；±dCa(2+)(i)/dt(max)）降低。肌浆网Ca(2+)-ATP酶表达未改变，而卵巢切除术后PLB和Ser16磷酸化PLB水平较高。雌激素治疗可恢复卵巢切除术的所有影响。
结论
卵巢切除术通过增加SERCA2a抑制剂PLB的表达来损害心肌Ca(2+)清除。有缺陷的Ca(2+)转运导致缺血性Ca(2+)(i)过载和缺血后Ca(2+)(i)瞬变恢复不足，从而导致血液动力学恢复受损。雌激素对心肌完整Ca(2+)循环的保护在增强IT中起主要作用。
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