FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway

Hui, Xuejun; Hu, Fengjiao; Liu, Jia; Li, Changhai; Yang, Yang; Shu, Shangzhi; Li, Peipei; Wang, Fan; Li, Shuyan

doi:10.1016/j.yjmcc.2020.09.008

Cited by 8 publications

(7 citation statements)

References 39 publications

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“…Pathological cardiac hypertrophy is also a common pathological process in the development of many cardiovascular diseases, such as ischemic heart disease and valvular heart disease. Persistent pathological hypertrophy eventually leads to cardiac dysfunction and increased morbidity due to heart failure [ 33 , 34 ]. Therefore, it is necessary to identify targets for prevention and treatment of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

“…The mice were observed until recovery on a heated pad set at 37 °C, and all mice were allocated randomly to the TAC or sham group. Mice were intraperitoneally injected with the GCN5-specific inhibitor MB3 at a concentration of 5 mg/kg once every 2 days; mice subjected to TAC were intraperitoneally injected with the TAK1 inhibitor 5Z-7-oxozeaenol at a concentration of 5 mg/kg for 4 weeks, n = 7–8 mice/group [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

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GCN5-mediated regulation of pathological cardiac hypertrophy via activation of the TAK1-JNK/p38 signaling pathway

Yan²,

Wang

et al. 2022

Cell Death Dis

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Pathological cardiac hypertrophy is a process of abnormal remodeling of cardiomyocytes in response to pressure overload or other stress stimuli, resulting in myocardial injury, which is a major risk factor for heart failure, leading to increased morbidity and mortality. General control nonrepressed protein 5 (GCN5)/lysine acetyltransferase 2 A, a member of the histone acetyltransferase and lysine acetyltransferase families, regulates a variety of physiological and pathological events. However, the function of GCN5 in pathological cardiac hypertrophy remains unclear. This study aimed to explore the role of GCN5 in the development of pathological cardiac hypertrophy. GCN5 expression was increased in isolated neonatal rat cardiomyocytes (NRCMs) and mouse hearts of a hypertrophic mouse model. GCN5 overexpression aggravated the cardiac hypertrophy triggered by transverse aortic constriction surgery. In contrast, inhibition of GCN5 impairs the development of pathological cardiac hypertrophy. Similar results were obtained upon stimulation of NRCMs (having GCN5 overexpressed or knocked down) with phenylephrine. Mechanistically, our results indicate that GCN5 exacerbates cardiac hypertrophy via excessive activation of the transforming growth factor β-activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK)/p38 signaling pathway. Using a TAK1-specific inhibitor in rescue experiments confirmed that the activation of TAK1 is essential for GCN5-mediated cardiac hypertrophy. In summary, the current study elucidated the role of GCN5 in promotion of cardiac hypertrophy, thereby implying it to be a potential target for treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

GCN5-mediated regulation of pathological cardiac hypertrophy via activation of the TAK1-JNK/p38 signaling pathway

Yan²,

Wang

et al. 2022

Cell Death Dis

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“…Our previous study found that PA can directly bind to myeloid differentiation 2 (MD2), activate the NF‐κB signaling pathway, increase P65 nuclear metastasis, and then produce inflammatory factors(Y. Wang et al, 2020). It is worth noting that TAK1, as a crucial protein in this pathway, can be regulated by various proteins, which can affect myocarditis, fibrosis, and myocardial hypertrophy(Hui et al, 2021; Wang et al, 2021; Zhao et al, 2021). A recent study found that A20 can inhibit the activation of its downstream pathway by downregulating the activity of TAK1, thereby preventing the development of obese cardiomyopathy(Xu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Tabersonine alleviates obesity‐induced cardiomyopathy by binding to Transforming growth factor activated kinase 1 (TAK1) and inhibiting TAK1‐mediated inflammation

Chen

Lin

Pan

et al. 2022

Phytotherapy Research

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Obesity‐induced cardiomyopathy (OIC) is an increasingly serious global disease caused by obesity. Chronic inflammation greatly contributes to the pathogenesis of OIC. This study aimed to explore the role and mechanism of tabersonine (Tab), a natural alkaloid with antiinflammatory activity, in the treatment of OIC. High fat diet (HFD)‐induced obese mice were administered with Tab. The results showed that Tab significantly inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of body weight and hyperlipidemia, in HFD‐induced obese mice. H9c2 cells and primary cardiomyocytes stimulated by palmitic acid (PA) were used to explore the molecular mechanism and target of Tab. We examined the effect of Tab on key proteins involved in HFD/PA‐induced inflammatory signaling pathway and found that Tab significantly inhibits TAK1 phosphorylation in cardiomyocytes. We further detected the direct interaction between Tab and TAK1 at the cellular, animal, and molecular levels. We found that Tab directly binds to TAK1 to inhibit TAK1 phosphorylation, which then blocks TAK1‐TAB2 interaction and then NF‐κB pro‐inflammatory pathway in cultured cardiomyocytes. Our results indicate that Tab is a potential agent for the treatment of OIC, and TAK1 is an effective therapeutic target for this disease.

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“…Mitogen‐activated protein kinases (MAPKs) consist of three kinases: the extracellular signal‐regulating kinases (ERKs), p38, and JUN N‐terminal kinases (JNKs) 13–15 . The activation of ERK1 and ERK2 takes place through their phosphorylation by upstream mitogen‐activated protein kinase kinases (MEK) 1 and 2 16 .…”

Section: Introductionmentioning

confidence: 99%

“…Mitogen-activated protein kinases (MAPKs) consist of three kinases: the extracellular signal-regulating kinases (ERKs), p38, and JUN N-terminal kinases (JNKs). [13][14][15] The activation of ERK1 and ERK2 takes place through their phosphorylation by upstream mitogen-activated protein kinase kinases (MEK) 1 and 2. 16 Overexpression of MEK1 and MEK2 results in adaptive concentric hypertrophy of the heart, and the interaction with the calcineurin/NFAT signalling pathway was shown to promote cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

Different activation of MAPKs and Akt/GSK3β after preload vs. afterload elevation

et al. 2022

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Aims Pressure overload (PO) and volume overload (VO) lead to concentric or eccentric hypertrophy. Previously, we could show that activation of signalling cascades differ in in vivo mouse models. Activation of these signal cascades could either be induced by intrinsic load sensing or neuro‐endocrine substances like catecholamines or the renin‐angiotensin‐aldosterone system. Methods and results We therefore analysed the activation of classical cardiac signal pathways [mitogen‐activated protein kinases (MAPKs) (ERK, p38, and JNK) and Akt‐GSK3β] in in vitro of mechanical overload (ejecting heart model, rabbit and human isolated muscle strips). Selective elevation of preload in vitro increased AKT and GSK3β phosphorylation after 15 min in isolated rabbit muscles strips (AKT 49%, GSK3β 26%, P < 0.05) and in mouse ejecting hearts (AKT 51%, GSK49%, P < 0.05), whereas phosphorylation of MAPKs was not influenced by increased preload. Selective elevation of afterload revealed an increase in ERK phosphorylation in the ejecting heart (43%, P < 0.05), but not in AKT, GSK3β, and the other MAPKs. Elevation of preload and afterload in the ejecting heart induced a significant phosphorylation of ERK (95%, P < 0.001) and showed a moderate increased AKT (P = 0.14) and GSK3β (P = 0.21) phosphorylation, which did not reach significance. Preload and afterload elevation in muscles strips from human failing hearts showed neither AKT nor ERK phosphorylation changes. Conclusions Our data show that preload activates the AKT–GSK3β and afterload the ERK pathway in vitro, indicating an intrinsic mechanism independent of endocrine signalling.

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FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway

Cited by 8 publications

References 39 publications

GCN5-mediated regulation of pathological cardiac hypertrophy via activation of the TAK1-JNK/p38 signaling pathway

GCN5-mediated regulation of pathological cardiac hypertrophy via activation of the TAK1-JNK/p38 signaling pathway

Tabersonine alleviates obesity‐induced cardiomyopathy by binding to Transforming growth factor activated kinase 1 (TAK1) and inhibiting TAK1‐mediated inflammation

Different activation of MAPKs and Akt/GSK3β after preload vs. afterload elevation

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