The role of sodium calcium exchanger (NCX)on cardiac function.

细胞膜上的Na~(++)-Ca~(2+)交换器(NCX)被认为是包括心肌细胞在内的许多哺乳动物可兴奋细胞从胞浆到胞外间隙的主要钙排出系统。目前已分离出三种NCX的哺乳动物亚型(NCX1、NCX2和NCX3)，NCX1在心脏中高水平表达。然而，由于缺乏NCX的特异性抑制剂，NCX在心脏中的病理生理作用仍不清楚。为探讨NCX在心脏收缩和心肌肥大中的作用，我们采用缩窄横主动脉的方法对NCX基因敲除杂合子(KO)小鼠心脏施加压力超负荷，并在术后3周检测心脏功能和形态。尽管假手术KO小鼠和假手术野生型(WT)小鼠的心功能没有差异，但KO小鼠在压力超负荷时表现出比WT小鼠更高的左心室压和更好的收缩功能。Northern印迹分析显示，压力超负荷使WT鼠左室肌浆网Ca^&lt；2+&Gt；-ATPase(SERCA2)的mRNA水平降低，而KO鼠无此作用。伴有间质纤维化的肥大改变在KO小鼠比WT小鼠更为显著。这些结果表明，Ncx的减少会导致心功能超常，并导致明显的心肌肥厚，以响应压力超负荷。

The Na^+-Ca^<2+> exchanger (NCX) on the plasma membrane is thought to be the main calcium extrusion system from the cytosol to the extracellular space in many mammalian excitable cells including cardiac myocytes. Three mammalian isoforms of NCX (NCX1, NCX2 and NCX3) have been isolated and NCX1 is expressed at high levels in the heart. However, the pathophysiological role of NCX in the heart is still unclear because of lack of specific inhibitors of NCX. To determine the role of NCX in cardiac contraction and the development of cardiac hypertrophy, we imposed pressure overload on the heart of heterozygous NCX knockout (KO) mice by constricting transverse aorta and examined cardiac function and morphology at three weeks after operation. Although there was no difference in cardiac function between sham-operated KO mice and sham-operated wild type (WT) mice, KO mice showed higher left ventricular pressure, and better systolic function than WT mice in response to pressure overload. Northern blot analysis revealed that mRNA levels of sarcoplasmic reticulum Ca^<2+>-ATPase (SERCA2) were reduced by pressure overload in left ventricles of WT mice but not of KO mice. Hypertrophic changes with interstitial fibrosis were more prominent in KO mice than WT mice. These results suggest that reduction of NCX results in supernormalized cardiac function and causes marked cardiac hypertrophy in response to pressure overload.