Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Circ Res. 2013 Jan 4;112(1):48-56. doi: 10.1161/CIRCRESAHA.112.272963. Epub 2012 Sep 19.
Mitogen-activated protein kinases (MAPKs) are activated in the heart by disease-inducing 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 serving a cardioprotective role.
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 lacking both Dusp1 and Dusp4 genes. Although single nulls showed no molecular effects, combined disruption of Dusp1/4 promoted unrestrained p38 MAPK activity in both mouse embryonic fibroblasts and the heart, with no change in the phosphorylation of c-Jun N-terminal kinases or extracellular signal-regulated kinases 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 also was partially rescued by 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.
有丝分裂原激活的蛋白激酶(MAPKs)在心脏中被疾病诱导和应激诱导的刺激所激活,在心脏中它们参与肥大、重构、收缩和心力衰竭。双特异性磷酸酶(DUSPs)家族直接使每种 MAPK 末端效应物失活,可能具有心脏保护作用。
确定 DUSP1 和 DUSP4 在调节 p38 MAPK 在心脏中的功能及其对疾病的影响中的作用。
在这里,我们生成了缺乏 Dusp1 和 Dusp4 基因的小鼠和小鼠胚胎成纤维细胞。尽管单个缺失没有表现出分子效应,但 Dusp1/4 的联合缺失促进了小鼠胚胎成纤维细胞和心脏中 p38 MAPK 活性的不受限制,在基线或应激刺激下,c-Jun N-末端激酶或细胞外信号调节激酶的磷酸化没有变化。单独缺失 Dusp1 或 Dusp4 不会导致心脏病理学,尽管 Dusp1/4 双敲除小鼠随着年龄的增长表现出心肌病和死亡率增加。用 SB731445 抑制 p38 MAPK 的药理学抑制作用改善了 Dusp1/4 双敲除小鼠的心肌病,表明 DUSP1/4 主要通过 p38 MAPK 影响疾病。在细胞水平上,不受限制的 p38 MAPK 活性降低了心脏的收缩性和 Ca2+ 处理,这可以通过 p38 抑制化合物急性逆转。Dusp1/4 双敲除小鼠的功能不良也部分通过磷酸化酶磷蛋白缺失得到挽救。
我们的数据表明,Dusp1 和 Dusp4 是心脏保护性基因,通过抑制 p38 MAPK 信号,在心脏中发挥关键作用,否则会降低收缩性并诱导心肌病。