Selective HDAC8 Inhibition Attenuates Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis via p38 MAPK Pathway

Histone deacetylase (HDAC) expression and enzymatic activity are dysregulated in cardiovascular diseases. Among Class I HDACs, HDAC2 has been reported to play a key role in cardiac hypertrophy; however, the exact function of HDAC8 remains unknown. Here we investigated the role of HDAC8 in cardiac hypertrophy and fibrosis using the isoproterenol-induced cardiac hypertrophy model system.Isoproterenol-infused mice were injected with the HDAC8 selective inhibitor PCI34051 (30 mg kg−1 body weight). Enlarged hearts were assessed by HW/BW ratio, cross-sectional area, and echocardiography. RT-PCR, western blotting, histological analysis, and cell size measurements were performed. To elucidate the role of HDAC8 in cardiac hypertrophy, HDAC8 knockdown and HDAC8 overexpression were also used. Isoproterenol induced HDAC8 mRNA and protein expression in mice and H9c2 cells, while PCI34051 treatment decreased cardiac hypertrophy in isoproterenol-treated mice and H9c2 cells. PCI34051 treatment also reduced the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), transcription factors (Sp1, Gata4, and Gata6), and fibrosis markers (collagen type I, fibronectin, and Ctgf) in isoproterenol-treated mice. HDAC8 overexpression stimulated cardiac hypertrophy in cells, whereas HDAC8 knockdown reversed those effects. HDAC8 selective inhibitor and HDAC8 knockdown reduced the isoproterenol-induced activation of p38 MAPK, whereas HDAC8 overexpression promoted p38 MAPK phosphorylation. Furthermore, p38 MAPK inhibitor SB203580 significantly decreased the levels of p38 MAPK phosphorylation, as well as ANP and BNP protein expression, induced by HDAC8 overexpression.Here we show that inhibition of HDAC8 activity or expression suppresses cardiac hypertrophy and fibrosis. These findings suggest that HDAC8 could be a promising target to treat cardiac hypertrophy and fibrosis by regulating p38 MAPK.

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Stimulation of pro-α1(I) collagen by TGF-β1 in mesangial cells: role of the p38 MAPK pathway

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.3.f495 ◽

2001 ◽

Vol 280 (3) ◽

pp. F495-F504 ◽

Cited By ~ 92

Author(s):

Beek Yoke Chin ◽

Amir Mohsenin ◽

Su Xia Li ◽

Augustine M. K. Choi ◽

Mary E. Choi

Keyword(s):

P38 Mapk ◽

Intracellular Signaling ◽

Mesangial Cells ◽

Mapk Pathway ◽

Dominant Negative ◽

Glomerular Mesangial Cells ◽

Mapk Activation ◽

Mapk Phosphorylation ◽

Collagen Mrna

Transforming growth factor-β1(TGF-β1) is a potent inducer of extracellular matrix protein synthesis and a key mediator of renal fibrosis. However, the intracellular signaling mechanisms by which TGF-β1stimulates this process remain incompletely understood. In this report, we examined the role of a major stress-activated intracellular signaling cascade, belonging to the mitogen-activated protein kinase (MAPK) superfamily, in mediating TGF-β1 responses in rat glomerular mesangial cells, using dominant-negative inhibition of TGF-β1 signaling receptors. We first stably transfected rat glomerular mesangial cells with a kinase-deleted mutant TGF-β type II receptor (TβR-IIM) designed to inhibit TGF-β1 signaling in a dominant-negative fashion. Next, expression of TβR-IIM mRNA was confirmed by Northern analysis. Cell surface expression and ligand binding of TβR-IIM protein were demonstrated by affinity cross-linking with 125I-labeled-TGF-β1. TGF-β1 rapidly induced p38 MAPK phosphorylation in wild-type and empty vector (pcDNA3)-transfected control mesangial cells. Interestingly, transfection with dominant-negative TβR-IIM failed to block TGF-β1-induced p38 MAPK phosphorylation. Moreover, dominant-negative TβR-IIMfailed to block TGF-β1-stimulated pro-α1(I) collagen mRNA expression and cellular protein synthesis, whereas TGF-β1-induced extracellular signal-regulated kinase (ERK) 1/ERK2 activation and antiproliferative responses were blocked by TβR-IIM. In the presence of a specific inhibitor of p38 MAPK, SB-203580, TGF-β1 was unable to stimulate pro-α1(I) collagen mRNA expression in the control and TβR-IIM-transfected mesangial cells. Finally, we confirmed that both p38 MAPK activation and pro-α1(I) collagen stimulation were TGF-β1 effects that were abrogated by dominant-negative inhibition of TGF-β type I receptor. Thus we show first demonstration of p38 MAPK activation by TGF-β1 in mesangial cells, and, given the rapid kinetics, this TGF-β1 effect is likely a direct one. Furthermore, our findings suggest that the p38 MAPK pathway functions as a component in the signaling of pro-α1(I) collagen induction by TGF-β1 in mesangial cells.

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Swimming stress in DN 14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00550.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. H1269-H1277 ◽

Cited By ~ 12

Author(s):

Ken-ichi Watanabe ◽

Meilei Ma ◽

Ken-ichi Hirabayashi ◽

Narasimman Gurusamy ◽

Punniyakoti T. Veeraveedu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

P38 Mapk ◽

Cardiac Remodeling ◽

Mapk Pathway ◽

Left Ventricular ◽

Dominant Negative ◽

Checkpoint Control ◽

Mapk Activation ◽

Swimming Stress

It is generally believed that a mechanical signal initiates a cascade of biological events leading to coordinated cardiac remodeling. 14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. To evaluate the molecular mechanism underlying swimming stress-induced cardiac remodeling, we examined the role of 14-3-3 protein and MAPK pathway by pharmacological and genetic means using transgenic mice with cardiac-specific expression of dominant-negative (DN) mutants of 14-3-3 (DN 14-3-3/TG) and p38α/β MAPK (DNp38α and DNp38β) mice. p38 MAPK activation was earlier, more marked, and longer in the myocardium of the TG group compared with that of the nontransgenic (NTG) group after swimming stress, whereas JNK activation was detected on day 5 and decreased afterward. In contrast, ERK1/2 was not activated after swimming stress in either group. Cardiomyocyte apoptosis, cardiac hypertrophy, and fibrosis were greatly increased in the TG group compared with those in the NTG group. Moreover, we found a significant correlation between p38 MAPK activation and apoptosis in the TG group. Furthermore, DN 14-3-3 hearts showed enhanced atrial natriuretic peptide expression. In contrast, DNp38α and DNp38β mice exhibited reduced mortality and increased resistance to cardiac remodeling after 28 days of swimming stress compared with TG and NTG mice. Besides, treatment with a p38 MAPK inhibitor, FR-167653, resulted in regression of cardiac hypertrophy and fibrosis and improvement in the survival rate in the TG group. These results indicate for the first time that 14-3-3 protein along with p38 MAPK plays a crucial role in left ventricular remodeling associated with swimming stress.

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Role of the p38 MAPK Pathway in Induction of iNOS Expression in Human Leukocytes

Folia Biologica ◽

10.3409/fb56_1-2.83-89 ◽

2008 ◽

Vol 56 (1) ◽

pp. 83-89 ◽

Cited By ~ 6

Author(s):

Ewa Jablonska ◽

Wioletta Ratajczak ◽

Jakub Jablonski

Keyword(s):

P38 Mapk ◽

Mapk Pathway ◽

Inos Expression ◽

Human Leukocytes ◽

P38 Mapk Pathway

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Somatostatin stimulates intestinal NHE8 expression via p38 MAPK pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00421.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. C375-C382 ◽

Cited By ~ 15

Author(s):

Chunhui Wang ◽

Hua Xu ◽

Huacong Chen ◽

Jing Li ◽

Bo Zhang ◽

...

Keyword(s):

P38 Mapk ◽

Mapk Pathway ◽

Somatostatin Receptor ◽

Peptide Hormone ◽

Mitogen Activated Protein Kinase ◽

Mapk Phosphorylation ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein ◽

D Cells ◽

Human Intestinal Cells

Diarrhea is a common manifestation of gastrointestinal disorders. Diarrhea-induced losses of fluid and electrolyte could lead to dehydration and electrolyte imbalances, resulting in significant morbidity and mortality, especially in children living in developing countries. Somatostatin, a peptide hormone secreted by D-cells, plays an important role in regulating motility and intestinal Na+ absorption. Although octreotide, a somatostatin analog, is used to treat diarrhea, its mechanisms of action are unclear. Here we showed that octreotide increased brush-border membrane Na+/H+ exchanger 8 (NHE8) expression in the small intestine to the exclusion of other NHEs that participate in Na+ absorption. The same effect also occurred in human intestinal cells (Caco-2). We found that the increase of NHE8 expression by somatostatin required p38 mitogen-activated protein kinase (MAPK) activation. Furthermore, the somatostatin receptor SSTR2 antagonist CYN154806 could abolish somatostatin-induced NHE8 expression and p38 MAPK phosphorylation. Thus our data provided the first concrete evidence indicating that somatostatin stimulates intestinal Na+ absorption by increasing intestinal NHE8 expression through the SSTR2-p38 MAPK pathway.

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Anti-inflammatory role of Leptin in glial cells through p38 MAPK pathway inhibition

Pharmacological Reports ◽

10.1016/j.pharep.2016.12.005 ◽

2017 ◽

Vol 69 (3) ◽

pp. 409-418 ◽

Cited By ~ 7

Author(s):

Iván Patraca ◽

Nohora Martínez ◽

Oriol Busquets ◽

Aleix Martí ◽

Ignacio Pedrós ◽

...

Keyword(s):

P38 Mapk ◽

Glial Cells ◽

Mapk Pathway ◽

P38 Mapk Pathway ◽

Anti Inflammatory ◽

Pathway Inhibition

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Enhanced GRP78 protein expression via the IRE1α/ASK1/p38 MAPK pathway during As2O3-induced endoplasmic reticulum stress in BEAS-2B cells

Toxicology ◽

10.1016/j.tox.2021.152962 ◽

2021 ◽

Vol 462 ◽

pp. 152962

Author(s):

Jiaming Yuan ◽

Chenjuan Yao ◽

Jing Tang ◽

Yingqi Liu ◽

Chunyan Huang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Protein Expression ◽

P38 Mapk ◽

Mapk Pathway ◽

P38 Mapk Pathway

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Seasonal variations of p38 MAPK phosphorylation and heat shock protein expression in red blood cells of Sparus aurata.

Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology ◽

10.1016/j.cbpa.2010.06.141 ◽

2010 ◽

Vol 157 ◽

pp. S49-S50

Author(s):

K. Feidantsis ◽

T. Markou ◽

H.O. Pörtner ◽

A. Lazou ◽

B. Michaelidis

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Protein Expression ◽

Red Blood Cells ◽

P38 Mapk ◽

Seasonal Variations ◽

Blood Cells ◽

Sparus Aurata ◽

Mapk Phosphorylation ◽

Heat Shock Protein Expression

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Estrogen Enhances Matrix Synthesis in Nucleus Pulposus Cell through the Estrogen Receptor β-p38 MAPK Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000447915 ◽

2016 ◽

Vol 39 (6) ◽

pp. 2216-2226 ◽

Cited By ~ 11

Author(s):

Pei Li ◽

Yuan Xu ◽

Yibo Gan ◽

Liyuan Wang ◽

Bin Ouyang ◽

...

Keyword(s):

Estrogen Receptor ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Matrix Synthesis ◽

P38 Mapk Pathway ◽

Collagen Ii

Background/Aims: Matrix homeostasis within the disc nucleus pulposus (NP) tissue is important for disc function. Increasing evidence indicates that sex hormone can influence the severity of disc degeneration. This study was aimed to study the role of 17β-estradiol (E2) in NP matrix synthesis and its underlying mechanism. Methods: Rat NP cells were cultured with (10-5, 10-7 and 10-9 M) or without (control) E2 for48 hours. The estrogen receptor (ER)-β antagonist PHTPP and ERβ agonist ERB 041 were used to investigate the role mediated by ERβ. The p38 MAPK inhibitor SB203580 was used to investigate the role of p38 MAPK signaling pathway. Gene and protein expression of SOX9, aggrecan and collagen II, glycosaminoglycan (GAG) content, and immunostaining assay for aggrecan and collagen II were analyzed to evaluate matrix production in rat NP cells. Results: E2 enhanced NP matrix synthesis in a concentration-dependent manner regarding gene and proetin expression of SOX9, aggrecan and collagen II, protein deposition of aggrecan and collagen II, and GAG content. Moreover, activation of p38 MAPK signaling pathway was increased with elevating E2 concentration. Further analysis indicated that ERB 041 and PHTPP could respectively enhance and suppress effects of E2 on matrix synthesis in NP cells, as well as activation of p38 MAPK pathway. Additionally, inhibition of p38 MAPK signaling pathway significantly abolished the effects of E2 on matrix synthesis. Conclusion: E2 can enhance matrix synthesis of NP cells and the ERβ/p38 MAPK pathway is involved in this regulatory process.

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