Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A
Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A
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DOI：
10.1161/hh2301.100003
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发表时间：
2001-11-23
影响因子：
20.1
通讯作者：
Olson, EN
中科院分区：
文献类型：
--
作者：
Antos, CL;Frey, N;Olson, EN
β-肾上腺素能受体（β AR）信号传导（其升高细胞内cAMP并增强心脏收缩力）在衰竭的心脏中严重受损。蛋白激酶A（PKA）被cAMP激活，但PKA激活对心脏功能的长期生理效应尚不清楚。为了研究在缺乏与β AR信号传导相关的上游事件的情况下慢性心脏PKA激活的后果，我们产生了在心脏中表达PKA催化亚基的转基因小鼠。这些小鼠发展为扩张型心肌病，心肌收缩力降低，心律失常，易猝死。正如在人类心力衰竭中所见，这些异常与PKA介导的心脏ryanodine受体/Ca 2+释放通道的过度磷酸化相关，该通道增强肌浆网的Ca 2+释放，受磷蛋白调节肌浆网Ca 2 +-ATP酶。这些发现表明PKA在心力衰竭发病机制中的特定作用，独立于β AR信号传导中的更近端事件，并支持PKA活性参与慢性β AR信号传导的不良反应的观点。
beta -Adrenergic receptor (beta AR) signaling, which elevates intracellular cAMP and enhances cardiac contractility, is severely impaired in the failing heart. Protein kinase A (PKA) is activated by cAMP, but the long-term physiological effect of PKA activation on cardiac function is unclear. To investigate the consequences of chronic cardiac PKA activation in the absence of upstream events associated with beta AR signaling, we generated transgenic mice, that expressed the catalytic subunit of PKA in the heart. These mice developed dilated cardiomyopathy with reduced cardiac contractility, arrhythmias, and susceptibility to sudden death. As seen in human heart failure, these abnormalities correlated with PKA-mediated hyperphosphorylation of the cardiac ryanodine receptor/Ca2+-release channel, which enhances Ca2+ release from the sarcoplasmic reticulum, and phospholamban, which regulates the sarcoplasmic reticulum Ca2+-ATPase. These findings demonstrate a specific role for PKA in the pathogenesis of heart failure, independent of more proximal events in beta AR signaling, and support the notion that PKA activity is involved in the adverse effects of chronic beta AR signaling.