scholarly journals Angiotensin II activates myostatin expression in cultured rat neonatal cardiomyocytes via p38 MAP kinase and myocyte enhance factor 2 pathway

2008 ◽  
Vol 197 (1) ◽  
pp. 85-93 ◽  
Author(s):  
Bao-Wei Wang ◽  
Hang Chang ◽  
Peiliang Kuan ◽  
Kou-Gi Shyu
Keyword(s):  
Angiotensin Ii ◽  
Map Kinase ◽  
Cardiac Myocyte ◽  
Critical Role ◽  
Muscle Growth ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Neonatal Cardiomyocytes ◽  
Cardiac Myocyte Hypertrophy

Angiotensin II (AngII) plays a critical role in cardiac remodeling and promotes cardiac myocyte hypertrophy. Myostatin, a negative regulator of muscle growth, is increased in hypertrophied and infarcted heart. The direct effect of AngII on cardiac myocyte myostatin expression has not been previously investigated. We hypothesized that myostatin may act as a cardiac endocrine inhibitor for AngII. AngII-induced myostatin protein expression in cultured rat neonatal cardiomyocytes was dose-dependent. AngII significantly increased myostatin protein and mRNA expression in a time-dependent manner. Addition of losartan, SB203580, or p38 siRNA 30 min before AngII stimulation significantly blocked the increase of myostatin protein by AngII. AngII significantly increased phosphorylation of p38 while SB205380 and losartan attenuated the phosphorylation of p38 induced by AngII. AngII increased, while myostatin-Mut plasmid, SB203580, losartan, and myocyte enhance factor 2 (MEF-2) antibody abolished the myostatin promoter activity. Co-stimulation with myostatin and AngII significantly inhibited the protein synthesis induced by AngII. In conclusion, AngII enhances myostatin expression in cultured rat neonatal cardiomyocytes. The AngII-induced myostatin is mediated through p38 MAP kinase and MEF-2 pathway.

scholarly journals MAP kinase phosphatase MKP-1 regulates p-ERK1/2 signaling pathway with fluoride treatment

2020 ◽  
Author(s):  
Lin Zhao ◽  
Jiali Su ◽  
Sijia Liu ◽  
Yang Li ◽  
Tao Li ◽  
...  
Keyword(s):  
Map Kinase ◽  
Molecular Mechanisms ◽  
Tooth Enamel ◽  
Dental Fluorosis ◽  
Critical Role ◽  
Negative Regulator ◽  
Erk Signaling ◽  
High Dose ◽  
Dependent Manner ◽  
Map Kinase Phosphatase

Abstract Background Dental fluorosis is characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation. Excess fluoride could have effects on the ERK signaling, which is essential for the ameloblasts differentiation and tooth development. MAP kinase phosphatase-1 (MKP-1) plays a critical role in regulating ERK related kinases. However, the role of MKP-1 in ameloblast and the mechanisms of MKP-1/ERK signaling in the pathogenesis of dental fluorosis are incompletely understood. Results Here, we adopted an in vitro fluorosis cell model using murine ameloblasts-like LS8 cells by employing sodium fluoride (NaF) as inducer. Using this system, we demonstrated that fluoride exposure led to an inhibition of p- MEK and p-ERK1/2 with a subsequent increase in MKP-1 expression in a dose-dependent manner. We further identified, under high dose fluoride, MKP-1 acted as a negative regulator of the fluoride-induced p-ERK1/2 signaling, leading to downregulation of CREB, c-myc, and Elk-1. Conclusion Our results identify a novel MKP-1/ERK signaling mechanism that regulates dental fluorosis and provide a framework for studying the molecular mechanisms of intervention and fluorosis remodeling under normal and pathological conditions. MKP-1 inhibitors may prove to be a benefit therapeutic strategy for dental fluorosis treatment.

Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3512-3519 ◽  
Author(s):  
Roberta Caruso ◽  
Carmine Stolfi ◽  
Massimiliano Sarra ◽  
Angelamaria Rizzo ◽  
Massimo C. Fantini ◽  
...  
Keyword(s):  
Map Kinase ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Human Peripheral Blood ◽  
Serum Levels ◽  
Cell Types ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Therapeutic Implications

Abstract IL-25, a member of the IL-17 cytokine family, is known to enhance Th2-like responses associated with increased serum levels of IgE, IgG1, IgA, blood eosinophilia, and eosinophilic infiltrates in various tissues. However, IL-25 also abrogates inflammatory responses driven by Th17 cells. However, the cell types that respond to IL-25 and the mechanisms by which IL-25 differentially regulates immune reactions are not well explored. To identify potential targets of IL-25, we initially examined IL-25 receptor (IL-25R) in human peripheral blood cells. IL-25R was predominantly expressed by CD14+ cells. We next assessed the functional role of IL-25 in modulating the response of CD14+ cells to various inflammatory signals. CD14+ cells responded to IL-25 by down-regulating the synthesis of inflammatory cytokines induced by toll-like receptor (TLR) ligands and inflammatory cytokines. Inhibition of cytokine response by IL-25 occurred via a p38 Map kinase–driven Socs-3–dependent mechanism. In vivo, IL-25 inhibited monocyte-derived cytokines and protected against LPS-induced lethal endotoxemia in mice. These data indicate that IL-25 is a negative regulator of monocyte proinflammatory cytokine responses, which may have therapeutic implications.

p38 MAP kinase inhibitor reverses stress-induced cardiac myocyte dysfunction

2005 ◽  
Vol 98 (1) ◽  
pp. 77-82 ◽  
Author(s):  
Hong Kan ◽  
Dale Birkle ◽  
Abnash C. Jain ◽  
Conard Failinger ◽  
Sherry Xie ◽  
...  
Keyword(s):  
Map Kinase ◽  
Cardiac Myocyte ◽  
Kinase Inhibitor ◽  
Ventricular Myocytes ◽  
Myocardial Dysfunction ◽  
P38 Map Kinase ◽  
Border Detection ◽  
Rat Ventricular Myocytes ◽  
Adult Rat ◽  
Fractional Shortening

Stress is gaining increasing acceptance as an independent risk factor contributing to adverse cardiovascular outcomes. Potential mechanisms responsible for the deleterious effects of stress on the development and progression of cardiovascular disease remain to be elucidated. An established animal model of stress in humans is the prenatally stressed (PS) rat. We stressed rats in their third trimester of pregnancy by daily injections of saline and moving from cage to cage. Male offspring of these stressed dams (PS) and age-matched male control offspring (control) were further subjected to restraint stress (R) at 6 and 7 wk of age. Echocardiography revealed a significant decrease in fractional shortening in PS + R vs. controls + R (45.8 ± 3.9 vs. 61.9 ± 2.4%, PS + R vs. controls + R; P < 0.01; n = 12). Isolated adult rat ventricular myocytes from PS + R also revealed diminished fractional shortening (6.7 ± 0.8 vs. 12.7 ± 1.1%, PS + R vs. controls + R; P < 0.01; n = 24) and blunted inotropic responses to isoproterenol ( P < 0.01; n = 24) determined by automated border detection. The p38 mitogen-activated protein (MAP) kinase inhibitor SB-203580 blocked p38 MAP kinase phosphorylation, reversed the depression in fractional shortening, and partially ameliorated the blunted adrenergic signaling seen in adult rat ventricular myocytes from PS + R. Phosphorylation of p38 MAP kinase in cardiac myocytes by stress may be sufficient to lead to myocardial dysfunction in animal models and possibly humans.

scholarly journals Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca2+-mediated p38 MAP kinase activation

2019 ◽  
Author(s):  
Nicola M. Blythe ◽  
Vasili Stylianidis ◽  
Melanie J. Ludlow ◽  
Hamish T. J. Gilbert ◽  
Elizabeth L. Evans ◽  
...  
Keyword(s):  
Map Kinase ◽  
Structural Integrity ◽  
Kinase Inhibitor ◽  
Cardiac Fibroblasts ◽  
Collagen Gel ◽  
Mechanical Stretch ◽  
Cardiac Fibroblast ◽  
Ruthenium Red ◽  
P38 Map Kinase ◽  
Dependent Manner

AbstractPiezo1 is a mechanosensitive cation channel with widespread physiological importance; however its role in the heart is poorly understood. Cardiac fibroblasts are responsible for preserving the structural integrity of the myocardium and play a key role in regulating its repair and remodeling following stress or injury. We investigated expression and function of Piezo1 in cultured human and mouse cardiac fibroblasts. RT-PCR studies confirmed expression ofPiezo1mRNA in cardiac fibroblasts at similar levels to endothelial cells. Fura-2 intracellular Ca2+measurements validated Piezo1 as a functional ion channel that was activated by the Piezo1 agonist, Yoda1. Yoda1-induced Ca2+entry was inhibited by Piezo1 blockers (gadolinium, ruthenium red) and the Ca2+response was reduced proportionally by Piezo1 siRNA knockdown or in cells fromPiezo1+/−mice. Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation opposed cardiac fibroblast differentiation; data confirmed by functional collagen gel contraction assays. Piezo1 activation using Yoda1 or mechanical stretch also increased the expression of interleukin-6 (IL-6), a mechanosensitive pro-hypertrophic and pro-fibrotic cytokine, in a Piezo1-dependent manner. Multiplex kinase activity profiling combined with kinase inhibitor studies and phospho-specific western blotting, established that Piezo1 activation stimulated IL-6 secretion via a pathway involving p38 MAP kinase, downstream of Ca2+entry. In summary, this study reveals that cardiac fibroblasts express functional Piezo1 channels coupled to reduced myofibroblast activation and increased secretion of paracrine signaling molecules that can modulate cardiac remodeling.

scholarly journals Muscle Hyperplasia in Japanese Quail by Single Amino Acid Deletion in MSTN Propeptide

2020 ◽  
Vol 21 (4) ◽  
pp. 1504 ◽  
Author(s):  
Joonbum Lee ◽  
Dong-Hwan Kim ◽  
Kichoon Lee
Keyword(s):  
Muscle Mass ◽  
Gene Knockout ◽  
Muscle Growth ◽  
Avian Species ◽  
Negative Regulator ◽  
Single Amino Acid ◽  
Heart Weight ◽  
Dependent Manner ◽  
Base Pair Deletion ◽  
Muscle Hyperplasia

Mutation in myostatin (MSTN), a negative regulator of muscle growth in skeletal muscle, resulted in increased muscle mass in mammals and fishes. However, MSTN mutation in avian species has not been reported. The objective of this study was to generate MSTN mutation in quail and investigate the effect of MSTN mutation in avian muscle growth. Recently, a new targeted gene knockout approach for the avian species has been developed using an adenoviral CRISPR/Cas9 system. By injecting the recombinant adenovirus containing CRISPR/Cas9 into the quail blastoderm, potential germline chimeras were generated and offspring with three base-pair deletion in the targeted region of the MSTN gene was identified. This non-frameshift mutation in MSTN resulted in deletion of cysteine 42 in the MSTN propeptide region and homozygous mutant quail showed significantly increased body weight and muscle mass with muscle hyperplasia compared to heterozygous mutant and wild-type quail. In addition, decreased fat pad weight and increased heart weight were observed in MSTN mutant quail in an age- and sex-dependent manner, respectively. Taken together, these data indicate anti-myogenic function of MSTN in the avian species and the importance of cysteine 42 in regulating MSTN function.

scholarly journals Mechanisms underlying modulation of monocarboxylate transporter 1 (MCT1) by somatostatin in human intestinal epithelial cells

2009 ◽  
Vol 297 (5) ◽  
pp. G878-G885 ◽  
Author(s):  
Seema Saksena ◽  
Saritha Theegala ◽  
Nikhil Bansal ◽  
Ravinder K. Gill ◽  
Sangeeta Tyagi ◽  
...  
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitor ◽  
Apical Membrane ◽  
P38 Map Kinase ◽  
Monocarboxylate Transporter ◽  
Maximal Velocity ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Human Intestine ◽  
Monocarboxylate Transporter 1

Somatostatin (SST), an important neuropeptide of the gastrointestinal tract has been shown to stimulate sodium chloride absorption and inhibit chloride secretion in the intestine. However, the effects of SST on luminal butyrate absorption in the human intestine have not been investigated. Earlier studies from our group and others have shown that monocarboxylate transporter (MCT1) plays an important role in the transport of butyrate in the human intestine. The present studies were undertaken to examine the effects of SST on butyrate uptake utilizing postconfluent human intestinal epithelial Caco2 cells. Apical SST treatment of Caco-2 cells for 30–60 min significantly increased butyrate uptake in a dose-dependent manner with maximal increase at 50 nM (∼60%, P < 0.05). SST receptor 2 agonist, seglitide, mimicked the effects of SST on butyrate uptake. SST-mediated stimulation of butyrate uptake involved the p38 MAP kinase-dependent pathway. Kinetic studies demonstrated that SST increased the maximal velocity ( Vmax) of the transporter by approximately twofold without any change in apparent Michaelis-Menten constant ( Km). The higher butyrate uptake in response to SST was associated with an increase in the apical membrane levels of MCT1 protein parallel to a decrease in the intracellular MCT1 pool. MCT1 has been shown to interact specifically with CD147 glycoprotein/chaperone to facilitate proper expression and function of MCT1 at the cell surface. SST significantly enhanced the membrane levels of CD147 as well as its association with MCT1. This association was completely abolished by the specific p38 MAP kinase inhibitor, SB203580. Our findings demonstrate that increased MCT1 association with CD147 at the apical membrane in response to SST is p38 MAP kinase dependent and underlies the stimulatory effects of SST on butyrate uptake.

scholarly journals Heat Shock Protein 70 Negatively Regulates TGF-β-Stimulated VEGF Synthesis via p38 MAP Kinase in Osteoblasts

2017 ◽  
Vol 44 (3) ◽  
pp. 1133-1145 ◽  
Author(s):  
Go Sakai ◽  
Haruhiko Tokuda ◽  
Kazuhiko Fujita ◽  
Shingo Kainuma ◽  
Tetsu Kawabata ◽  
...  
Keyword(s):  
Growth Factor ◽  
Heat Shock ◽  
Map Kinase ◽  
Transforming Growth Factor ◽  
Mrna Level ◽  
Transforming Growth Factor Β ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Vegf Mrna ◽  
Vegf Release

Background/Aims: We previously demonstrated that transforming growth factor-β (TGF-β) stimulates the synthesis of vascular endothelial growth factor (VEGF) through the activation of p38 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. Heat shock protein70 (HSP70) is a ubiquitously expressed molecular chaperone. In the present study, we investigated the involvement of HSP70 in the TGF-β-stimulated VEGF synthesis and the underlying mechanism in these cells. Methods: Culture MC3T3-E1 cells were stimulated by TGF-β. Released VEGF was measured using an ELISA assay. VEGF mRNA level was quantified by RT-PCR. Phosphorylation of each protein kinase was analyzed by Western blotting. Results: VER-155008 and YM-08, both of HSP70 inhibitors, significantly amplified the TGF-β-stimulated VEGF release. In addition, the expression level of VEGF mRNA induced by TGF-β was enhanced by VER-155008. These inhibitors markedly strengthened the TGF-β-induced phosphorylation of p38 MAP kinase. The TGF-β-induced phosphorylation of p38 MAP kinase was amplified in HSP70-knockdown cells. SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by these inhibitors of the TGF-β-induced VEGF release. Conclusion: These results strongly suggest that HSP70 acts as a negative regulator in the TGF-β-stimulated VEGF synthesis in osteoblasts, and that the inhibitory effect of HSP70 is exerted at a point upstream of p38 MAP kinase.

scholarly journals PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

2016 ◽  
Vol 113 (45) ◽  
pp. E7116-E7125 ◽  
Author(s):  
Walter E. Knight ◽  
Si Chen ◽  
Yishuai Zhang ◽  
Masayoshi Oikawa ◽  
Meiping Wu ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Causative Role ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Cardiac Myocyte Hypertrophy

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.

Interaction and Regulation of HSC with Osteopontin Is Mediated through α4β1 and α9β1Integrins, Which Are Differentially Expressed in the HSC Pool.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1330-1330
Author(s):  
David N. Haylock ◽  
Genevieve A. Whitty ◽  
Brenda Williams ◽  
Melonie J. Storan ◽  
Susie K. Nilsson
Keyword(s):  
Cord Blood ◽  
Critical Role ◽  
Negative Regulator ◽  
Hemopoietic Stem Cell ◽  
Null Mouse ◽  
Dependent Manner ◽  
Independent Manner ◽  
Hsc Niche

Abstract Osteoblasts are a key cellular component of the hemopoietic stem cell (HSC) niche and directly regulate the HSC pool. Molecules synthesised by osteoblasts both promote or inhibit HSC proliferation. Osteopontin (Opn) is an osteoblast produced, RGD containing protein with roles in cell adhesion and migration. Until recently, the role of Opn in hemopoiesis was seen as restricted to the regulation of bone turnover. However, from analysis of hemopoiesis in the Opn null mouse, we have demonstrated that Opn plays a critical role in regulating the HSC pool. Furthermore Opn is critical in trans-marrow migration and lodgement of HSC within the BM after transplantation. When added to in vitro HSC cultures, exogenous thrombin-cleaved Opn also inhibits cell proliferation and potently suppresses HSC differentiation. We have now demonstrated that this interaction occurs in an RGD-independent manner via the cryptic SVVYGLR epitope revealed on the N-terminal fragment of Opn following thrombin cleavage. This epitope has previously been shown to bind to α4β1 and α9β1. HSC are known to express α4β1, but we have now shown that within the HSC pool this occurs in a differential manner, mimicking that of CD38, with more committed CD34+CD38+ cord blood progenitors having the highest levels of expression. In addition, we have shown the previously unrecognised characteristic of human marrow and cord blood HSC, the expression of α9β1, which also occurs in a differential manner, but mimicking CD34. Expression of α9β1 is highest on cord blood CD34+CD38− cells, a population highly enriched for HSC. Using the synthetic SVVYGLR peptide in culture, we re-capitulated the thrombin-cleaved Opn induced suppression of HSC differentiation in a dose dependent manner. Antibody blocking experiments demonstrated that binding to this peptide was occurring through both α4β1 and α9β1. In contrast, suppression of HSC proliferation and differentiation did not occur through the upstream alternate α4β1 binding site. Furthermore, we have now demonstrated endogenous binding of Opn to α4β1 and α9β1 to cord blood HSC in vivo. Together, these data provide strong evidence that Opn is an important component of the HSC niche which acts as a physiological negative regulator. Furthermore, our studies identify the previously unrecognised characteristic of HSC, the expression of α9β1, which together with α4β1 provides two receptors on HSC with differing expression signatures and potentially a mechanism for fine tunning the physiological effects of Opn.

Activation of p38 MAP Kinase and JNK But Not ERK Is Required for Erythropoietin-Induced Erythroid Differentiation

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 1859-1869 ◽  
Author(s):  
Yuka Nagata ◽  
Noriko Takahashi ◽  
Roger J. Davis ◽  
Kazuo Todokoro
Keyword(s):  
Cell Growth ◽  
Map Kinase ◽  
Antisense Oligonucleotides ◽  
Map Kinases ◽  
Physiological Function ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Erythroid Differentiation ◽  
P38 Map Kinase ◽  
American Society

p38 MAP kinase (p38) and JNK have been described as playing a critical role in the response to a variety of environmental stresses and proinflammatory cytokines. It was recently reported that hematopoietic cytokines activate not only classical MAP kinases (ERK), but also p38 and JNK. However, the physiological function of these kinases in hematopoiesis remains obscure. We found that all MAP kinases examined, ERK1, ERK2, p38, JNK1, and JNK2, were rapidly and transiently activated by erythropoietin (Epo) stimulation in SKT6 cells, which can be induced to differentiate into hemoglobinized cells in response to Epo. Furthermore, p38-specific inhibitor SB203580 but not MEK-specific inhibitor PD98059 significantly suppressed Epo-induced differentiation and antisense oligonucleotides of p38, JNK1, and JNK2, but neither ERK1 nor ERK2 clearly inhibited Epo-induced hemoglobinization. However, in Epo-dependent FD-EPO cells, inhibition of either ERKs, p38, or JNKs suppressed cell growth. Furthermore, forced expression of a gain-of-function MKK6 mutant, which specifically activated p38, induced hemoglobinization of SKT6 cells without Epo. These results indicate that activation of p38 and JNKs but not of ERKs is required for Epo-induced erythroid differentiation of SKT6 cells, whereas all of these kinases are involved in Epo-induced mitogenesis of FD-EPO cells. © 1998 by The American Society of Hematology.

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