scholarly journals JNK signaling-dependent regulation of histone acetylation are involved in anacardic acid alleviates cardiomyocyte hypertrophy induced by phenylephrine

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261388
Author(s):  
Bohui Peng ◽  
Chang Peng ◽  
Xiaomei Luo ◽  
Shuqi Wu ◽  
Qian Mao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Histone Acetylation ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Anacardic Acid ◽  
Mitogen Activated Protein Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Jnk Signaling ◽  
Hat Inhibitor

Cardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetyltransferase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the related upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling pathway in cardiac hypertrophy induced by PE. The mice cardiomyocyte hypertrophy model was successfully established by treating cells with PE in vitro. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9ac hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, and β-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiomyocyte hypertrophy. In particular, AA inhibits the effects of JNK signaling on HATs-mediated histone acetylation, and could therefore be used to prevent and treat pathological cardiac hypertrophy.

scholarly journals Anacardic acid protects against phenylephrine-induced mouse cardiac hypertrophy through JNK signaling-dependent regulation of histone acetylation

2020 ◽  
Author(s):  
Bohui Peng ◽  
Chang Peng ◽  
Xiaomei Luo ◽  
Lixin Huang ◽  
Qian Mao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Histone Acetylation ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Anacardic Acid ◽  
Mitogen Activated Protein Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Jnk Signaling ◽  
Hat Inhibitor

AbstractCardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetylase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling in cardiac hypertrophy. A mouse model of cardiomyocyte hypertrophy was successfully established in vitro using PE. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9 hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, and β-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiac hypertrophy. In particular, AA inhibits the effects of JNK signaling on HAT-mediated histone acetylation, and could therefore be used to prevent and treat hypertrophic cardiomyopathy.

scholarly journals Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

2006 ◽  
Vol 11 (4) ◽  
pp. 423-434 ◽  
Author(s):  
Charlotta Grånäs ◽  
Betina Kerstin Lundholt ◽  
Frosty Loechel ◽  
Hans-Christian Pedersen ◽  
Sara Petersen Bjørn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Protein Kinase Signaling

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution® assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution® assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC50 =< 5 μM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution® screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant.

scholarly journals MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

2021 ◽  
Author(s):  
William E. Tidyman ◽  
Alice F. Goodwin ◽  
Yoshiko Maeda ◽  
Ophir D. Klein ◽  
Katherine A. Rauen
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Skeletal Myopathy ◽  
Mitogen Activated Protein

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

scholarly journals Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3βand MAPK Signaling Pathways

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Wen-Ying Wei ◽  
Zhen-Guo Ma ◽  
Si-Chi Xu ◽  
Ning Zhang ◽  
Qi-Zhu Tang
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Glycogen Synthase ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Aortic Banding ◽  
Hypertrophic Response

Peroxisome proliferator activated receptorγ(PPARγ) has been closely involved in the process of cardiovascular diseases. This study was to investigate whether pioglitazone (PIO), a PPARγagonist, could protect against pressure overload-induced cardiac hypertrophy. Mice were orally given PIO (2.5 mg/kg) from 1 week after aortic banding and continuing for 7 weeks. The morphological examination and biochemical analysis were used to evaluate the effects of PIO. Neonatal rat ventricular cardiomyocytes were also used to verify the protection of PIO against hypertrophy in vitro. The results in our study demonstrated that PIO remarkably inhibited hypertrophic response induced by aortic banding in vivo. Besides, PIO also suppressed cardiac fibrosis in vivo. PIO treatment also inhibited the activation of protein kinase B (AKT)/glycogen synthase kinase-3β(GSK3β) and mitogen-activated protein kinase (MAPK) in the heart. In addition, PIO alleviated angiotensin II-induced hypertrophic response in vitro. In conclusion, PIO could inhibit cardiac hypertrophy via attenuation of AKT/GSK3βand MAPK pathways.

scholarly journals Parkia speciosa Hassk. Empty Pod Extract Alleviates Angiotensin II-Induced Cardiomyocyte Hypertrophy in H9c2 Cells by Modulating the Ang II/ROS/NO Axis and MAPK Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Hawa Nordin Siti ◽  
Juriyati Jalil ◽  
Ahmad Yusof Asmadi ◽  
Yusof Kamisah
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Mapk Pathway ◽  
Reactive Oxygen ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Oxygen Species ◽  
Ang Ii

Cardiac hypertrophy is characteristic of heart failure in patients who have experienced cardiac remodeling. Many medicinal plants, including Parkia speciosa Hassk., have documented cardioprotective effects against such pathologies. This study investigated the activity of P. speciosa empty pod extract against cardiomyocyte hypertrophy in H9c2 cardiomyocytes exposed to angiotensin II (Ang II). In particular, its role in modulating the Ang II/reactive oxygen species/nitric oxide (Ang II/ROS/NO) axis and mitogen-activated protein kinase (MAPK) pathway was examined. Treatment with the extract (12.5, 25, and 50 μg/ml) prevented Ang II-induced increases in cell size, NADPH oxidase activity, B-type natriuretic peptide levels, and reactive oxygen species and reductions in superoxide dismutase activity. These were comparable to the effects of the valsartan positive control. However, the extract did not significantly ameliorate the effects of Ang II on inducible nitric oxide synthase activity and nitric oxide levels, while valsartan did confer such protection. Although the extract decreased the levels of phosphorylated extracellular signal-related kinase, p38, and c-Jun N-terminal kinase, valsartan only decreased phosphorylated c-Jun N-terminal kinase expression. Phytochemical screening identified the flavonoids rutin (1) and quercetin (2) in the extract. These findings suggest that P. speciosa empty pod extract protects against Ang II-induced cardiomyocyte hypertrophy, possibly by modulating the Ang II/ROS/NO axis and MAPK signaling pathway via a mechanism distinct from valsartan.

scholarly journals Combined VEGFR and MAPK pathway inhibition in angiosarcoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael J. Wagner ◽  
Yasmin A. Lyons ◽  
Jean H. Siedel ◽  
Robert Dood ◽  
Archana S. Nagaraja ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Combined Treatment ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
In Vivo Model ◽  
Mitogen Activated Protein

AbstractAngiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.

scholarly journals Bone Marrow Mesenchymal Stem Cells Inhibit the Function of Dendritic Cells by Secreting Galectin-1

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Yue Zhang ◽  
Xia-hui Ge ◽  
Xue-Jun Guo ◽  
Si-bin Guan ◽  
Xiao-ming Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Dendritic Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mouse Bone Marrow

This study aimed to investigate whether bone marrow-derived mesenchymal stem cells (BM-MSCs) can inhibit function of dendritic cells (DCs) by secreting Galectin-1 (Gal-1). BM-MSCs have been shown to inhibit the maturation and function of DCs, further inhibiting the activation and proliferation of T cells. However, the detailed mechanism remains unknown. In this current study, MSCs and DCs derived from mouse bone marrow were cocultured using Transwell culture plates under different in vitro conditions. The results showed that as the ratio of MSC to DC of the coculture system increased and the coculture time of the two cells prolonged, the concentrations of Gal-1, interleukin- (IL-) 10, and IL-12 in the supernatants were increased and the protein expression of Gal-1 on and within DCs was also enhanced. The phosphorylation of extracellular signal-regulated kinase (ERK) pathway in DCs was boosted, whereas p38 mitogen-activated protein kinase (MAPK) pathway phosphorylation was weakened. Meanwhile, the expression of costimulatory molecules on the surface of DCs was decreased, and the proliferative effect of DCs on allogeneic T cells was also decreased. Therefore, this present study indicated that Gal-1 secreted from MSCs upregulated expression of Gal-1 and stimulated formation of tolerance immunophenotype on DCs, where the underlying mechanism was the regulation of the MAPK signaling pathway in DCs, thereby inhibiting the function of DCs.

scholarly journals Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

2021 ◽  
Author(s):  
Sarah A. Carratt ◽  
Theodore P. Braun ◽  
Cody Coblentz ◽  
Zachary Schonrock ◽  
Rowan Callahan ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Gene Expression Signature ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Juvenile Myelomonocytic Leukemia ◽  
Murine Bone Marrow ◽  
Relapsed Disease

AbstractMutations in SET binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging pre-clinical data for the use of trametinib in SETBP1-mutant disease.

scholarly journals Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway

2020 ◽  
Vol 21 (20) ◽  
pp. 7483 ◽  
Author(s):  
Wen-Chih Liu ◽  
Jia-Fwu Shyu ◽  
Yuh-Feng Lin ◽  
Hui-Wen Chiu ◽  
Paik Seong Lim ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Indoxyl Sulfate ◽  
Mitogen Activated Protein Kinase ◽  
Uremic Toxin ◽  
Aryl Hydrocarbon ◽  
The Impact

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 μM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients.

Dual-specificity phosphatases are targets of the Wnt/β-catenin pathway and candidate mediators of β-catenin/Ras signaling interactions

2012 ◽  
Vol 393 (10) ◽  
pp. 1183-1191 ◽  
Author(s):  
Eva Zeller ◽  
Katharina Mock ◽  
Moritz Horn ◽  
Sabine Colnot ◽  
Michael Schwarz ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Dual Specificity ◽  
Murine Liver ◽  
Dual Specificity Phosphatases

Abstract The Wnt/β-catenin and the Ras/mitogen-activated protein kinase (MAPK) pathways play important roles in cancer development. Both pathways have been studied discretely, but the mechanisms of possible crosstalk are still not fully understood. We have previously shown that β-catenin and MAPK signaling interfere with each other in murine liver in vivo and in vitro. Here, we show that dual specificity phosphatases (Dusps) 6 and 14, known to play an essential role in regulating MAPK pathway activity via feedback mechanisms, are up-regulated by activation of β-catenin in murine liver cells, whereas the epidermal growth factor receptor, an upstream effector in the Ras/MAPK cascade, is down-regulated by β-catenin. In addition, we identified a β-catenin-binding site within the Dusp6 promoter, which is responsible for the activation of the promoter by β-catenin signaling, and demonstrated reduced inducibility of MAPK signaling in cultured mouse hepatoma cells following β-catenin activation. Thus, β-catenin is able to inhibit activation of the Egfr/Ras/MAPK signaling cascade, both at the receptor level and by interfering with MAPK activity via Dusps.

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