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

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.

• Authors: Chang-Yi Li, Qing Zhou, Ling-Chao Yang, Yi-He Chen, Jian-Wen Hou, Kai Guo, Yue-Peng Wang, Yi-Gang Li
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 111 Issue 2 Pg. 19 (Mar 2016) ISSN: 1435-1803 [Electronic] Germany
• PMID: 26891723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Angiotensin II
• Animals
• Base Sequence
• Cardiomegaly (enzymology)
• Case-Control Studies
• Cells, Cultured
• Dual-Specificity Phosphatases (genetics, 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