Increased inhibition of SERCA2 by phospholamban in the type I diabetic heart
Increased inhibition of SERCA2 by phospholamban in the type I diabetic heart
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DOI：
10.1023/b:mcbi.0000028762.97754.26
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发表时间：
2004-06-01
影响因子：
4.3
通讯作者：
Netticadan, T
中科院分区：
文献类型：
--
作者：
Vasanji, Z;Dhalla, NS;Netticadan, T
肌浆网（SR）在调节心肌收缩力中起着重要作用，糖尿病心脏SR功能异常。然而，糖尿病心脏SR功能障碍的机制尚不清楚。由于蛋白磷酸化调节SR功能，本研究检测了受磷蛋白的磷酸化状态，受磷蛋白是调节心脏SR钙（Ca 2+）摄取的关键SR蛋白。雄性Sprague-Dawley大鼠通过注射链脲佐菌素（STZ; 65 mg kg（-1）i. v.），6周后人道处死动物，检测心脏SR功能。抑郁的心脏性能与减少SR Ca 2+摄取活动在糖尿病动物。SR Ca 2+摄取的减少与SRCa 2+泵ATP酶（SERCA 2a）蛋白水平的显著降低一致。受磷蛋白（PLB）水平也降低，但PLB与SERCA 2a的比例增加。抑制SR钙摄取也是由于钙调蛋白依赖性蛋白激酶（CaMK）和cAMP依赖性蛋白激酶（PKA）磷酸化PLB的减少。虽然SR相关的Ca 2 +-钙调素依赖性蛋白激酶（CaMK）、cAMP依赖性蛋白激酶（PKA）的活性在糖尿病心脏中增加，但PLB磷酸化的抑制可能部分归因于SR相关的蛋白磷酸酶活性的增加。这些结果表明PLB对SERCA 2a的抑制增加，这似乎是糖尿病心脏SR功能障碍的主要缺陷。
The sarcoplasmic reticulum (SR) plays a critical role in mediating cardiac contractility and its function is abnormal in the diabetic heart. However, the mechanisms underlying SR dysfunction in the diabetic heart are not clear. Because protein phosphorylation regulates SR function, this study examined the phosphorylation state of phospholamban, a key SR protein that regulates SR calcium (Ca2+) uptake in the heart. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (STZ; 65 mg kg(-1) i. v.), and the animals were humanely killed after 6 weeks and cardiac SR function was examined. Depressed cardiac performance was associated with reduced SR Ca2+-uptake activity in diabetic animals. The reduction in SR Ca2+-uptake was consistent with a significant decrease in the level of SRCa2+-pump ATPase (SERCA2a) protein. The level of phospholamban (PLB) protein was also decreased, however, the ratio of PLB to SERCA2a was increased in the diabetic heart. Depressed SR Ca2+-uptake was also due to a reduction in the phosphorylation of PLB by the Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein kinase (PKA). Although the activities of the SR-associated Ca2+-calmodulin-dependent protein kinase (CaMK), cAMP-dependent protein kinase (PKA) were increased in the diabetic heart, depressed phosphorylation of PLB could partly be attributed to an increase in the SR-associated protein phosphatase activities. These results suggest that there is increased inhibition of SERCA2a by PLB and this appears to be a major defect underlying SR dysfunction in the diabetic heart.