Mishra Sudhish, Gupta Ramesh C, Tiwari Nivedita, Sharov Victor G, Sabbah Hani N
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA
J Heart Lung Transplant. 2002 Mar;21(3):366-73. doi: 10.1016/s1053-2498(01)00390-4.
Human failing heart due to idiopathic dilated cardiomyopathy is associated with decreased sarcoplasmic reticulum Ca(2+) uptake. However, it is unknown as to which mechanism leads to this abnormality.
Immunodetectable sarcoplasmic reticulum proteins (phospholamban [PLB], phosphorylated PLB at serine-16 or threonine-17, calsequestrin and Ca(2+)-ATPase levels), the activities of Ca(2+)-calmodulin-dependent protein kinase and protein phosphatase and Ca(2+) uptake at varying Ca(2+) concentrations were determined in left ventricular specimens from the same 7 failing hearts (ejection fraction 20 +/- 2%) due to idiopathic dilated cardiomyopathy and 5 non-failing explanted control donor hearts.
In failing hearts, compared with control donors, decreased maximal velocity and affinity of Ca(2+) uptake for Ca(2+) were found to be associated with reduced expression levels of Ca(2+)-adenosine triphosphatase (ATPase), PLB and phosphorylated PLB at serine-16, but not of calsequestrin and phosphorylated PLB at threonine-17. In contrast, protein phosphatase activity increased significantly and the activity and protein expression level of the delta isoform of Ca(2+)-calmodulin-dependent protein kinase remained unchanged in failing hearts compared with control donors.
The impaired maximal velocity of sarcoplasmic reticulum Ca(2+) uptake may be due in part to reduced protein expression level of Ca(2+)-ATPase, whereas the reduced affinity may be due in part to the reduced ratio of Ca(2+)-ATPase to PLB and reduced PLB phosphorylation at serine-16 in failing hearts. The latter abnormality may be due in part to increased protein phosphatase activity. These results suggest that selective enhancement of Ca(2+) uptake into the sarcoplasmic reticulum by pharmaceutical agents, or by molecular tools that inhibit phosphatase activity, would be a valuable therapeutic approach for treating, or at least retarding, the process of heart failure.
特发性扩张型心肌病导致的人类衰竭心脏与肌浆网钙摄取减少有关。然而，导致这种异常的机制尚不清楚。
在7例因特发性扩张型心肌病导致的衰竭心脏（射血分数20±2%）和5例非衰竭的外植对照供体心脏的左心室标本中，测定了可免疫检测的肌浆网蛋白（受磷蛋白[PLB]、丝氨酸-16或苏氨酸-17磷酸化的PLB、肌集钙蛋白和钙-ATP酶水平）、钙调蛋白依赖性蛋白激酶和蛋白磷酸酶的活性以及不同钙浓度下的钙摄取。
与对照供体相比，在衰竭心脏中，发现钙摄取对钙的最大速度和亲和力降低与钙-三磷酸腺苷酶（ATP酶）、PLB和丝氨酸-16磷酸化的PLB表达水平降低有关，但与肌集钙蛋白和苏氨酸-17磷酸化的PLB无关。相反，与对照供体相比，衰竭心脏中蛋白磷酸酶活性显著增加，钙调蛋白依赖性蛋白激酶δ亚型的活性和蛋白表达水平保持不变。
肌浆网钙摄取的最大速度受损可能部分归因于钙-ATP酶蛋白表达水平降低，而亲和力降低可能部分归因于衰竭心脏中钙-ATP酶与PLB的比例降低以及丝氨酸-16处PLB磷酸化减少。后一种异常可能部分归因于蛋白磷酸酶活性增加。这些结果表明，通过药物或抑制磷酸酶活性的分子工具选择性增强钙摄取到肌浆网中，将是治疗或至少延缓心力衰竭进程的一种有价值的治疗方法。
