Unrestrained p38 MAPK activation in Dusp1/4 double-null mice induces cardiomyopathy.
Unrestrained p38 MAPK activation in Dusp1/4 double-null mice induces cardiomyopathy.
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DOI：
10.1161/circresaha.112.272963
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发表时间：
2013-01-04
影响因子：
20.1
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Auger-Messier M;Accornero F;Goonasekera SA;Bueno OF;Lorenz JN;van Berlo JH;Willette RN;Molkentin JD
丝裂原活化蛋白激酶(MAPK)在心脏中被疾病和应激刺激激活，参与肥大、重塑、收缩和心力衰竭。一系列双特异性磷酸酶(DUSP)直接使每个MAPK末端效应器失活，具有潜在的心脏保护作用。目的：探讨DUSP1和DUSP4在心脏p38MAPK功能调节中的作用及其对疾病的影响。在这里，我们产生了缺乏DUSP1和Dusp4基因的小鼠和小鼠胚胎成纤维细胞(MEF)。当单个缺失没有表现出分子效应时，联合破坏DUSP1/4促进了MEF和心脏中不受抑制的p38MAPK活性，而c-jun氨基末端激酶(JNK)或细胞外信号调节激酶(ERK1/2)的磷酸化在基线或应激刺激下没有变化。DUSP1或Dusp4的单独干扰不会导致心脏病理，尽管DUSP1/4双零小鼠表现出心肌病，并随着年龄的增长而增加死亡率。SB731445对p38MAPK的抑制可改善DUSP1/4双缺失小鼠的心肌病，提示DUSP1/4主要通过p38MAPK发挥作用。在细胞水平上，不受抑制的p38MAPK活性降低了心肌的收缩能力和对钙的处理能力，这一点被p38抑制化合物急剧逆转。在DUSP1/4双缺失小鼠中，PLN基因的缺失也部分挽救了其功能低下的状态。我们的数据表明，DUSP1和Dusp4是心脏保护基因，它们通过抑制p38MAPK信号在心脏中发挥关键作用，否则p38MAPK信号将降低收缩能力并引发心肌病。
Mitogen-activated protein kinases (MAPKs) are activated in the heart by disease- and stress-inducing stimuli where they participate in hypertrophy, remodeling, contractility, and heart failure. A family of dual-specificity phosphatases (DUSPs) directly inactivates each of the MAPK terminal effectors, potentially being cardioprotective. To determine the role of DUSP1 and DUSP4 in regulating p38 MAPK function in the heart and the effect on disease. Here we generated mice and mouse embryonic fibroblasts (MEFs) lacking both Dusp1 and Dusp4 genes. While single nulls showed no molecular effects, combined disruption of Dusp1/4 promoted unrestrained p38 MAPK activity in both MEFs and the heart, with no change in the phosphorylation of c-Jun N-terminal kinases (JNK) or extracellular signal-regulated kinases (ERK1/2), at baseline or with stress stimulation. Single disruption of either Dusp1 or Dusp4 did not result in cardiac pathology, although Dusp1/4 double null mice exhibited cardiomyopathy and increased mortality with aging. Pharmacological inhibition of p38 MAPK with SB731445 ameliorated cardiomyopathy in Dusp1/4 double null mice indicating that DUSP1/4 function primarily through p38 MAPK in affecting disease. At the cellular level, unrestrained p38 MAPK activity diminished cardiac contractility and Ca2+ handling, which was acutely reversed with a p38 inhibitory compound. Poor function in Dusp1/4 double null mice was also partially rescued by Pln (phospholamban) deletion. Our data demonstrate that Dusp1 and Dusp4 are cardioprotective genes that play a critical role in the heart by dampening p38 MAPK signaling that would otherwise reduce contractility and induce cardiomyopathy.