Unrestrained p38 MAPK Activation in Dusp1/4 Double Null Mice Induces Cardiomyopathy
Rationale: 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.
Objective: To determine the role of DUSP1 and DUSP4 in regulating p38 MAPK function in the heart and the effect on disease.
Methods and Results: 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.
Conclusions: 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.
- Dilated cardiomyopathy
- MAP kinase kinase 6
- Mitogen-activated protein kinases
- Signal transduction
- Genetically altered mice
- Received May 2, 2012.
- Accepted September 19, 2012.
- Copyright © 2012, American Heart Association