title: 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.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
authors.forename: Chang-Yi
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
authors.forename: Ling-Chao
authors.initials: LC
authors.lastname: Yang
authors.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
authors.forename: Yi-He
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Hou
authors.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
authors.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
authors.forename: Yue-Peng
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Department of Cardiology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. drliyigang@outlook.com.
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Li
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000201:enzymology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006333:Heart Failure / Q000201:enzymology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000502:physiology; D051381:Rats; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000804:Angiotensin II; D054637:Dual-Specificity Phosphatases; D020930:MAP Kinase Kinase Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D000099151:MAP Kinase Kinase Kinase 7; C498843:DUSP14 protein, human; C498844:Dusp14 protein, mouse
keywords: Cardiac hypertrophy; Dual-specificity phosphatases; Mitogen-activated protein kinases; Signal transduction