Ablation of phospholamban and sarcolipin results in cardiac hypertrophy and decreased cardiac contractility
Ablation of phospholamban and sarcolipin results in cardiac hypertrophy and decreased cardiac contractility
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DOI：
10.1093/cvr/cvq294
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发表时间：
2011-02-01
影响因子：
10.8
通讯作者：
Babu, Gopal J.
中科院分区：
文献类型：
--
作者：
Shanmugam, Mayilvahanan;Gao, Shumin;Babu, Gopal J.
目的改善肌浆网(SR)钙-三磷酸腺苷酶(SERCA)功能对心力衰竭的治疗具有临床意义。本研究旨在探讨SERCA泵的结构性激活对正常小鼠和压力超负荷心脏高血压小鼠心脏收缩功能的影响。方法和结果通过阻断SERCA泵的关键调节因子磷脂酶A(PLN)和肌磷脂(SLN)，在小鼠心脏的房室和室腔中结构性地激活SERCA泵。PLN和SLN的双基因敲除(DKO)小鼠表现出SERCA泵活性、钙瞬变和肌浆网钙负荷增加，并出现心肌肥厚。超声心动图测量显示，幼年dko小鼠的基础心功能没有受到影响。结论SERCA泵的结构性激活对心功能有损害作用。我们的发现也强调了PLN和/或SLN动态调节SERCA泵的必要性，以维持正常条件下和病理生理状态下的心脏收缩能力。
Aims Improving the sarco(endo) plasmic reticulum (SR) Ca2+-ATPase (SERCA) function has clinical implications in treating heart failure. The present study aimed to determine the effect of constitutive activation of the SERCA pump on cardiac contractility in normal mice and during pressure-overload-induced cardiac hypertrophy.Methods and results The SERCA pump was constitutively activated in both atrial and ventricular chambers of the mouse heart by ablating its key regulators, phospholamban (PLN) and sarcolipin (SLN). The double-knockout (dKO) mice for PLN and SLN showed increased SERCA pump activity, Ca2+ transients and SR Ca2+ load, and developed cardiac hypertrophy. Echocardiographic measurements showed that the basal cardiac function was not affected in the young dKO mice. However, the cardiac function worsened upon ageing and when subjected to pressure overload.Conclusion Our studies suggest that the constitutive activation of the SERCA pump is detrimental to cardiac function. Our findings also emphasize the need for dynamic regulation of the SERCA pump by PLN and/or SLN to maintain cardiac contractility in normal conditions and during pathophysiological states.