Vangheluwe Peter, Schuermans Marleen, Raeymaekers Luc, Wuytack Frank
Laboratory of Physiology, University of Leuven, Herestraat 49, Bus 802 B-3000 Leuven, Belgium.
Cell Calcium. 2007 Sep;42(3):281-9. doi: 10.1016/j.ceca.2007.01.001. Epub 2007 Feb 15.
A reduced activity of the sarcoplasmic reticulum Ca2+ pump SERCA2a is a hallmark of cardiac dysfunction in heart failure. In SERCA2b/b mice, the normal SERCA2a isoform is replaced by SERCA2b, displaying a higher Ca2+ affinity. This elicited decreased cardiac SERCA2 expression and cardiac hypertrophy. Here, the interplay was studied between the increased Ca2+ affinity and a reduced expression of the pump and its role in the cardiac remodeling was investigated. First, SERCA2b/b mice were crossed with SERCA2b transgenes to boost cardiac SERCA2b expression. However, the enforced expression of SERCA2b was spontaneously countered by an increased inhibition by phospholamban (PLB), reducing the pump's Ca2+ affinity. Moreover, the higher SERCA2 content did not prevent hypertrophy. Second, we studied heterozygous SERCA2b/WT mice, which also express lower SERCA2 levels compared to wild-type. Hypertrophy was not observed. In heterozygotes, SERCA2b expression was specifically suppressed, explaining the reduced SERCA2 content. The SERCA2b/WT model strikingly differs from the homozygote models because SERCA2a (not SERCA2b) is the major isoform and because the inhibition of the pump by PLB is decreased instead of being increased. Thus, a tight correlation exists between the SERCA2 levels and Ca2+ affinity (controlled by PLB). This compensatory response may be important to prevent cardiac remodeling.
肌浆网Ca2+泵SERCA2a活性降低是心力衰竭时心脏功能障碍的一个标志。在SERCA2b/b小鼠中，正常的SERCA2a亚型被SERCA2b取代，表现出更高的Ca2+亲和力。这导致心脏SERCA2表达降低和心脏肥大。在此，研究了Ca2+亲和力增加与泵表达降低之间的相互作用，并研究了其在心脏重塑中的作用。首先，将SERCA2b/b小鼠与SERCA2b转基因杂交，以提高心脏SERCA2b的表达。然而，SERCA2b的强制表达被受磷蛋白（PLB）抑制增加而自发抵消，降低了泵的Ca2+亲和力。此外，较高的SERCA2含量并不能预防肥大。其次，我们研究了杂合子SERCA2b/WT小鼠，与野生型相比，其SERCA2水平也较低。未观察到肥大。在杂合子中，SERCA2b的表达被特异性抑制，这解释了SERCA2含量降低的原因。SERCA2b/WT模型与纯合子模型显著不同，因为SERCA2a（而非SERCA2b）是主要亚型，并且PLB对泵的抑制作用降低而非增加。因此，SERCA2水平与Ca2+亲和力（由PLB控制）之间存在紧密的相关性。这种代偿反应对于预防心脏重塑可能很重要。
