The effect of aging and pressure overload on the heart of SERCA2a mutant mice

肌浆网(SR)是一种广泛的细胞内膜系统，通过肌浆网(SR)循环，在维持正常的心脏功能和心脏疾病的发展中起着至关重要的作用。心脏肌浆网Ca~(2+)&gt；ATPase(SERCA2a)主要调节心肌松弛过程中胞浆Ca~(2+)~(2+)~(2+)~(2+)~(2+)再摄取速率。大量研究表明，SERCA2a活性降低是心力衰竭的共同特征，恢复SERCA2a活性可预防心力衰竭的发展。磷蛋白是抑制SERCA2a活性的主要内源性抑制物。最近的研究包括我们的研究表明，磷蛋白基因的突变与人类心肌病有关。我们在1例肥厚型心肌病患者中发现了SERCA2基因的杂合子单核苷酸突变。然后，我们产生了含有V540A突变体的转基因小鼠。除了新近发现的SR蛋白--磷蛋白外，Sarcalumenin还通过与SERCA2a的相互作用调节Ca~(2+)的再摄取。Sarcalumenin是一种钙结合糖蛋白，位于SR的管腔内，被认为调节SR中的Ca^lt；2+和Gt；的运输和储存。SERCA2a突变的TG和Sarcalumenin基因敲除的小鼠都表现出轻度的松弛显性心功能障碍。在这里，我们研究了衰老和压力超负荷应激对这些小鼠的影响。这些应激促进了Sarcalumenin KO小鼠的心功能障碍，进而提示了Sarcalumenin-SERCA2a相互作用在维持心功能中的重要作用。

Ca^<2+> cycling via the sarcoplasmic reticulum (SR), an extensive intracellular membrane system of Ca^<2+> store, plays a critical role in maintaining normal cardiac function as well as in development of heart diseases. Cardiac SR Ca^<2+> ATPase (SERCA2a) primarily regulates the rate of Ca^<2+> re-uptake from the cytosole to the SR lumen during relaxation in the heart. A considerable number of studies have demonstrated that the decrease in SERCA2a activity is a common feature of heart failure and that restoring SERCA2a activity prevents the development of heart failure. Phospholamban is a main endogenous inhibitor that suppresses the activity of SERCA2a. Recent studies including ours have demonstrated that mutations in the phospholamban gene are associated with human cardiomyopathy. We found a heterozygous single nucleotide transitions of the SERCA2 gene in one patients with hypertrophic cardiomyopathy. Then, we generated transgenic mice harboring V540A mutant. In addition to phospholamban, a newly identified SR protein, sarcalumenin also regulate Ca^<2+> re-uptake through the interaction with SERCA2a. Sarcalumenin is a Ca^<2+> binding glycoprotein located in the lumen of the SR and thought to regulate Ca^<2+> transport and storage in the SR. Both SERCA2a mutant TG and sarcalumenin knockout mice exhibit mild relaxation-dominant cardiac dysfunction. Here we examined the effect of aging and pressure overload stresses on these mice. These stresses promoted cardiac dysfunction in sarcalumenin KO mice, and then indicated the important role of sarcalumenin-SERCA2a interaction in maintaining cardiac function.