Minamisawa S, Hoshijima M, Chu G, Ward C A, Frank K, Gu Y, Martone M E, Wang Y, Ross J, Kranias E G, Giles W R, Chien K R
Department of Medicine, and Center for Molecular Genetics, University of California at San Diego, La Jolla 92093-0613C, USA.
Cell. 1999 Oct 29;99(3):313-22. doi: 10.1016/s0092-8674(00)81662-1.
Dilated cardiomyopathy and end-stage heart failure result in multiple defects in cardiac excitation-contraction coupling. Via complementation of a genetically based mouse model of dilated cardiomyopathy, we now provide evidence that progressive chamber dilation and heart failure are dependent on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. Inhibition of phospholamban-SERCA2a interaction via in vivo expression of a phospholamban point mutant dominantly activated the contractility of ventricular muscle cells. Thus, interfering with phospholamban-SERCA2a interaction may provide a novel therapeutic approach for preventing the progression of dilated cardiomyopathy.
扩张型心肌病和终末期心力衰竭会导致心脏兴奋-收缩偶联出现多种缺陷。通过对基于基因的扩张型心肌病小鼠模型进行互补研究，我们现在提供证据表明，进行性心腔扩张和心力衰竭依赖于心肌肌浆网中的钙离子循环缺陷。肌肉特异性肌浆网钙离子ATP酶（SERCA2a）抑制剂受磷蛋白的消融，挽救了类似于人类心力衰竭的一系列表型。通过体内表达磷蛋白点突变体抑制磷蛋白与SERCA2a的相互作用，可显著激活心室肌细胞的收缩力。因此，干扰磷蛋白与SERCA2a的相互作用可能为预防扩张型心肌病的进展提供一种新的治疗方法。
