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

2021 ◽  
Vol 151 ◽  
pp. 31-43
Author(s):  
Xuejun Hui ◽  
Fengjiao Hu ◽  
Jia Liu ◽  
Changhai Li ◽  
Yang Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Pathological Cardiac Hypertrophy

scholarly journals Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
L Shen ◽  
Y Shen ◽  
X Wang ◽  
B He
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Prostaglandin E1 ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
Ep3 Receptor

Abstract Aims Pathological cardiac hypertrophy induced by activation of the renin–angiotensin–aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. Methods and results Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E prostanoid (EP)3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. Conclusion In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1–MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals Delphinidin attenuates pathological cardiac hypertrophy via the AMPK/NOX/MAPK signaling pathway

Aging ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 5362-5383 ◽  
Author(s):  
Youming Chen ◽  
Zhuowang Ge ◽  
Shixing Huang ◽  
Lei Zhou ◽  
Changlin Zhai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Pathological Cardiac Hypertrophy

scholarly journals MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Yehong Du ◽  
Yexiang Du ◽  
Yun Zhang ◽  
Zhilin Huang ◽  
Min Fu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Amyloid Β ◽  
Gene Promoter ◽  
Long Term Potentiation ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase

AbstractMitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-β (Aβ)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both Aβ precursor protein (APP) and β-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced Aβ production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.

scholarly journals The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis

2003 ◽  
Vol 111 (6) ◽  
pp. 833-841 ◽  
Author(s):  
Shaosong Zhang ◽  
Carla Weinheimer ◽  
Michael Courtois ◽  
Attila Kovacs ◽  
Cindy E. Zhang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway

scholarly journals Sleeve Gastrectomy Ameliorates Diabetes-Induced Cardiac Hypertrophy Correlates With the MAPK Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Xu ◽  
Huanxin Ding ◽  
Songhan Li ◽  
Shuohui Dong ◽  
Linchuan Li ◽  
...  
Keyword(s):  
Sleeve Gastrectomy ◽  
Cardiac Hypertrophy ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Sham Group ◽  
Heart Function ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Metabolic Parameters ◽  
Myocardial Glucose Uptake

Background: Cardiac hypertrophy as a main pathological manifestation of diabetic cardiomyopathy (DCM), is a significant complication of diabetes. Bariatric surgery has been proven to relieve DCM; however, whether it can alleviate diabetes-induced cardiac hypertrophy is undefined.Methods: Diabetic and obese rats were performed sleeve gastrectomy (SG) after having diabetes for 16weeks. The rats were euthanized 8weeks after SG. Metabolic parameters, heart function parameters, myocardial glucose uptake, morphometric and histological changes, and the expression level of mitogen-activated protein kinases (MAPKs) were determined and compared among the control group (CON group), diabetes mellitus group (DM group), sham operation group (SHAM group), and SG group.Results: Compared with the SHAM group, the blood glucose, body weight, insulin resistance, and other metabolic parameters were significantly improved in the SG group. There was also a marked improvement in myocardial morphometric and histological parameters after SG. Furthermore, the myocardial glucose uptake and heart function were reversed after SG. Additionally, the phosphorylation of MAPKs was inhibited after SG, including p38 MAPKs, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases 1/2 (ERK1/2). The expression of DUSP6, which dephosphorylates ERK1/2, was upregulated after SG. These findings suggest that SG ameliorated diabetes-induced cardiac hypertrophy correlates with the MAPK signaling pathway.Conclusion: These results showed that diabetes-induced cardiac hypertrophy was ameliorated after SG was closely related to the inhibition of the MAPK signaling pathway and upregulation of DUSP6. Therefore, this study provides a novel strategy for treating diabetes-induced cardiac hypertrophy.

AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway

2011 ◽  
Vol 511 (1-2) ◽  
pp. 1-7 ◽  
Author(s):  
Rongsen Meng ◽  
Zhaohui Pei ◽  
Aixia Zhang ◽  
Yutian Zhou ◽  
Xingming Cai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Ampk Activation

CKIP-1 contributes to osteogenic differentiation of mouse bone marrow mesenchymal stem cells

2021 ◽  
Vol 16 (9) ◽  
pp. 847-859
Author(s):  
Qiannan Niu ◽  
Shuning Shen ◽  
Jiaojiao He ◽  
Lei Wang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Mouse Bone Marrow ◽  
Marrow Mesenchymal Stem Cells

Background: Osteogenesis greatly depends on the differentiation of bone marrow mesenchymal stem cells (BMSCs). CKIP-1 is considered to be a negative regulator of BMSCs. Methods: We established a  CKIP-1 knockout mouse model, then isolated and cultured BMSCs from wild-type and knockout groups. Results: Our data demonstrated that CKIP-1 knockout significantly increased bone structure in the experimental mouse model and enhanced BMSC proliferation. CKIP-1 knockout contributed to osteoblastic and adipogenic differentiation. Furthermore, CKIP-1 regulated osteogenesis in BMSCs via the MAPK signaling pathway, and BMSCs from the  CKIP-1 knockout mice were effective in repairing the skull defect null mice. Conclusion: Our results concluded that silencing of CKIP-1 promoted osteogenesis in experimental mice and increased BMSCs differentiation via upregulation of the MAPK signaling pathway.

Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress

Planta Medica ◽  
2017 ◽  
Vol 83 (10) ◽  
pp. 837-845 ◽  
Author(s):  
Hong Feng ◽  
Jianlei Cao ◽  
Guangyu Zhang ◽  
Yanggan Wang
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
In Vitro Study ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mouse Heart ◽  
H9c2 Cardiomyocytes

AbstractKaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function. Mice hearts were collected for pathological observation and molecular mechanism investigation. H9c2 cardiomyocytes were stimulated with or without phenylephrine for in vitro study. Kaempferol significantly attenuated cardiac hypertrophy induced by aorta banding as evidenced by decreased cardiomyocyte areas and interstitial fibrosis, accompanied with improved cardiac functions and decreased apoptosis. The ASK1/MAPK signaling pathways (JNK1/2 and p38) were markedly activated in the aorta banding mouse heart but inhibited by kaempferol treatment. In in vitro experiments, kaempferol also inhibited the activity of ASK1/JNK1/2/p38 signaling pathway and the enlargement of H9c2 cardiomyocytes. Furthermore, our study revealed that kaempferol could protect the mouse heart and H9c2 cells from pathological oxidative stress. Our investigation indicated that treatment with kaempferol protects against cardiac hypertrophy, and its cardioprotection may be partially explained by the inhibition of the ASK1/MAPK signaling pathway and the regulation of oxidative stress.

scholarly journals TRIM22 Activates MAPK Signaling by Regulating the Transcription of SPHK2 and Accelerating the Degradation of Raf-1 in Glioblastoma

2021 ◽  
Author(s):  
Xiaowei Fei ◽  
Ya-nan Dou ◽  
Kai Sun ◽  
Jialiang Wei ◽  
Qingdong Guo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathway ◽  
Mrna Level ◽  
Critical Role ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Exon 2

Abstract Background Tripartite motif (TRIM) 22 and mitogen-activated protein kinase (MAPK) signaling pathways play a critical role in tumor growth and therapeutic resistance of glioblastoma (GBM) respectively. However, the molecular mechanism between TRIM22 and MAPK signaling remains to be clarified. Methods We constructed TRIM22 knockout cell lines for molecular biology experiments, detected potential DNA fragments binding to TRIM22 by ChIP-Seq technology, and verified the sequencing results by ChIP-qPCR and CUT&Tag technology. In addition, we constructed different TRIM22 mutants to detect the binding of proteins in MAPK signaling pathway. Finally, the therapeutic effect was verified in NOD/SCID mice. The difference between the two groups of data conforming to the normal distribution was tested by Student t-test. Results Here, we found for the first time that TRIM22 acts as a transcription factor in the nucleus and binds to exon 2 of the transcript (NM_001204160) of SPHK2 gene to regulate its expression by ChIP-Seq technology, thus indirectly affecting the downstream MAPK signaling pathway. Knockout of TRIM22 using Cas9-sgRNAs resulted in decreased mRNA level of SPHK2 in GBM cells, while overexpression of TRIM22 enhanced it. The ERK1/2 driven luciferase reporter construct identified TRIM22 as a potential activator of MAPK signaling. Knockout and overexpression of TRIM22 regulate the inhibition and activation of MAPK signaling through its RING-finger domain. Co-immunoprecipitation demonstrated that TRIM22 bound to the negative regulator Raf-1 of MAPK signaling and accelerated its degradation by inducing K48-linked ubiquitination. The combination of the two is related to the CC domain and SPRY domain of TRIM22 and the C1D domain of Raf-1. TRIM22 also forms a complex with the downstream regulator ERK1/2 of MAPK and promotes K63-linked ubiquitination, resulting in the phosphorylation of ERK1/2. In addition, in vitro and in situ xenotransplantation models, SPHK2 inhibitor (K145), ERK1/2 inhibitor (Selumetinib) and non-phosphorylated mutant Raf-1S338A inhibited the growth promoting properties of TRIM22 in GBM cell line. Conclusions In conclusion, our study shows that TRIM22 regulates SPHK2 transcription as a transcription factor, indirectly affects MAPK signaling, and activates MAPK signaling through post-translational modification of two critical regulators of MAPK signaling in GBM cells.

Sign in / Sign up

Export Citation Format

Share Document