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.

Expression and regulation of type 2A protein phosphatases and alpha4 signalling in cardiac health and hypertrophy

“…4a and Supplemental Figure S6, was sufficient to significantly increase PP2AC subunit expression by 65.2% in our studies, which supports the observations of previous reports that the diseased myocardium is causally associated with enhanced PP2AC expression [18, 25] and activity [1, 7]. It is worth noting, that in a similar model of pressure overload where transaortic constriction was also maintained for 4 weeks, the protein expression of a non-type 2A protein phosphatase, the dual-specificity phosphatase 14 (Dusp14) was conversely reduced in hypertrophied tissue [46]. Furthermore, rapid pacing has been shown to also decrease the protein expression of another dual-specificity phosphatase MAPK phosphatase 1 (MKP1) [22].…”

Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs)

“…For example, Li et al characterized the role of DUSP14 in the heart in the hypertrophic response using both Dusp14 −/− mice as well as Tg mice with cardiac overexpression of this gene [27] ( Table 2 ). In cardiomyopathic human hearts, as well as in TAC-operated mouse hearts, DUSP14 expression was decreased.…”

“…Indeed, Dusp14 −/− mice exhibited cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction in response to 4 weeks of pressure overload injury. In contrast, DUSP14 Tg mice had attenuated cardiac hypertrophy and less dysfunction following stress [27]. Interestingly, loss of Dusp14 led to increased activity of TAK1, p38 and JNK1/2 without alterations in ERK1/2 phosphorylation in TAC operated mice, whereas hearts from DUSP14 Tg mice had reduced activity of TAK1, p38 and JNK1/2.…”

“…The second and cytoplasmic-localized group includes DUSP6/MKP-3, DUSP7 and DUSP9/MKP4, which are largely specific for ERK1/2 dephosphorylation [25]. The final group includes the cytoplasmic and nuclear localized DUSPs, including DUSP8 (M3/6), DUSP10/MKP5, DUSP14/MKP6, and DUSP16/MKP7, which are thought to have greater specificity for JNK and p38, although DUSP14 is also involved in inactivation of transforming growth factor beta-activated kinase 1 (TAK1) and DUSP8 appears to be more specific for ERK1/2 [27, 28]. The exact specificity of a given DUSP protein for selected MAPKs is often difficult to determine as it can vary between cell-types and depend on the type of assay empolyed.…”

Activin Receptor‐Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy

“…Briefly, mice assigned to AAC groups were anesthetized with 2% isoflurane inhalation. A 7‐0 silk suture was placed around the suprarenal abdominal aorta and tied around a 27‐gauge desharpened needle, which was then subsequently removed 1, 20. For sham operations, the suture was placed around the suprarenal abdominal aorta without ligation.…”