Vangheluwe P, Sipido K R, Raeymaekers L, Wuytack F
Laboratory of Physiology, University of Leuven, Herestraat 49, bus 802, B-3000 Leuven, Belgium.
Biochim Biophys Acta. 2006 Nov;1763(11):1216-28. doi: 10.1016/j.bbamcr.2006.08.025. Epub 2006 Aug 25.
Cardiomyocyte relaxation and contraction are tightly controlled by the activity of the cardiac sarco(endo)plasmic reticulum (SR) Ca2+ transport ATPase (SERCA2a). The SR Ca2+ -uptake activity not only determines the speed of Ca(2+) removal during relaxation, but also the SR Ca2+ content and therefore the amount of Ca2+ released for cardiomyocyte contraction. The Ca2+ affinity is the major determinant of the pump's activity in the physiological Ca2+ concentration range. In the heart, the affinity of the pump for Ca2+ needs to be controlled between narrow borders, since an imbalanced affinity may evoke hypertrophic cardiomyopathy. Several small proteins (phospholamban, sarcolipin) adjust the Ca2+ affinity of the pump to the physiological needs of the cardiomyocyte. It is generally accepted that a chronically reduced Ca2+ affinity of the pump contributes to depressed SR Ca2+ handling in heart failure. Moreover, a persistently lower Ca2+ affinity is sufficient to impair cardiomyocyte SR Ca2+ handling and contractility inducing dilated cardiomyopathy in mice and humans. Conversely, the expression of SERCA2a, a pump with a lower Ca2+ affinity than the housekeeping isoform SERCA2b, is crucial to maintain normal cardiac function and growth. Novel findings demonstrated that a chronically increased Ca2+ affinity also may trigger cardiac hypertrophy in mice and humans. In addition, recent studies suggest that some models of heart failure are marked by a higher affinity of the pump for Ca2+, and hence by improved cardiomyocyte relaxation and contraction. Depressed cardiomyocyte SR Ca2+ uptake activity may therefore not be a universal hallmark of heart failure.
心肌细胞的舒张和收缩受到心肌肌浆网（SR）钙转运ATP酶（SERCA2a）活性的严格控制。肌浆网的钙摄取活性不仅决定舒张期钙清除的速度，还决定肌浆网的钙含量，进而决定心肌细胞收缩时释放的钙量。在生理钙浓度范围内，钙亲和力是该泵活性的主要决定因素。在心脏中，该泵对钙的亲和力需要在狭窄范围内受到控制，因为亲和力失衡可能引发肥厚型心肌病。几种小蛋白（受磷蛋白、肌浆蛋白）可根据心肌细胞的生理需求调节该泵的钙亲和力。普遍认为，该泵长期降低的钙亲和力会导致心力衰竭时肌浆网钙处理功能受损。此外，持续较低的钙亲和力足以损害心肌细胞的肌浆网钙处理功能并导致收缩性降低，从而在小鼠和人类中诱发扩张型心肌病。相反，SERCA2a（一种钙亲和力低于管家异构体SERCA2b的泵）的表达对于维持正常心脏功能和生长至关重要。新的研究结果表明，长期增加的钙亲和力也可能在小鼠和人类中引发心脏肥大。此外，最近的研究表明，某些心力衰竭模型的特点是该泵对钙的亲和力较高，因此心肌细胞的舒张和收缩功能得到改善。因此，心肌细胞肌浆网钙摄取活性降低可能并非心力衰竭的普遍特征。
