Dual-specificity phosphatase 14 protects the heart from aortic banding-induced cardiac hypertrophy and dysfunction through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway

Basic Res Cardiol. 2016 Mar;111(2):19. doi: 10.1007/s00395-016-0536-7. Epub 2016 Feb 18.

Abstract

Dual-specificity phosphatase 14 (Dusp14), an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways, has been implicated in inflammatory immune response, cancers, cell differentiation and proliferation. The role of Dusp14 in chronic pressure overload-induced cardiac hypertrophy has not been explored. Here we have shown that Dusp14-/- knockout mice and cardiac-specific Dusp14 transgenic mice were generated and subjected to aortic banding (AB) for 4 weeks. Our results demonstrated that genetic loss of Dusp14 significantly aggravated cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction, whereas transgenic cardiac-specific Dusp14 overexpression significantly attenuated AB-induced cardiac dysfunction and remodeling. In vitro, adenoviral overexpression of constitutive Dusp14 blocked angiotensin II-induced hypertrophic growth of cardiomyocytes, while Dusp14 knockdown led to opposite effects. Mechanistically, excessive phosphorylation of TAK1, P38MAPK and JNK1/2 was evidenced in Dusp14-/- knockout mice post-AB and inactivation of TAK1-P38MAPK and -JNK1/2 signaling using TAK1 inhibitor 5Z-7-ox shares similar antihypertrophic effect as Dusp14 overexpression. Moreover, we show that Dusp14 directly interacted with TAK1. Results from present experiments indicate that Dusp14 protects the heart from AB-induced cardiac hypertrophy and dysfunction possibly through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway. Future studies are warranted to test the feasibility of overexpressing Dusp14 as a therapeutic strategy to attenuate cardiac hypertrophy and failure.

Keywords: Cardiac hypertrophy; Dual-specificity phosphatases; Mitogen-activated protein kinases; Signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Base Sequence
  • Cardiomegaly / enzymology*
  • Case-Control Studies
  • Cells, Cultured
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • HEK293 Cells
  • Heart Failure / enzymology*
  • Humans
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism*
  • Molecular Sequence Data
  • Myocytes, Cardiac / physiology
  • Rats

Substances

  • Angiotensin II
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP14 protein, human
  • Dual-Specificity Phosphatases
  • Dusp14 protein, mouse