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

2007 ◽  
Vol 292 (3) ◽  
pp. H1269-H1277 ◽  
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.

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

2001 ◽  
Vol 280 (3) ◽  
pp. F495-F504 ◽  
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.

Swimming Stress in DN 14-3-3 Mice Exacerbates Cardiac Remodeling: Role of p38 MAPK

2007 ◽  
Vol 13 (6) ◽  
pp. S29
Author(s):  
Rajarajan Amirthalingam Thandavarayan ◽  
Kenichi Watanabe ◽  
Punniyakoti Veeraveedu Thanickachalam
Keyword(s):  
P38 Mapk ◽  
Cardiac Remodeling ◽  
Swimming Stress

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Tingwei Zhao ◽  
Hae Jin Kee ◽  
Liyan Bai ◽  
Moon-Ki Kim ◽  
Seung-Jung Kee ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Protein Expression ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Selective Inhibitor ◽  
Type I ◽  
H9c2 Cells ◽  
Mapk Phosphorylation ◽  
Exact Function

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.

scholarly journals β-Arrestin2 Is Critically Involved in CXCR4-mediated Chemotaxis, and This Is Mediated by Its Enhancement of p38 MAPK Activation

2002 ◽  
Vol 277 (51) ◽  
pp. 49212-49219 ◽  
Author(s):  
Yue Sun ◽  
Zhijie Cheng ◽  
Lan Ma ◽  
Gang Pei
Keyword(s):  
P38 Mapk ◽  
Stromal Cell ◽  
Cancer Metastasis ◽  
Mapk Pathway ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mapk Activation ◽  
Endogenous Expression ◽  
Stromal Cell Derived Factor ◽  
Negative Mutant

Chemotaxis mediated by chemokine receptors such as CXCR4 plays a key role in lymphocyte homing and hematopoiesis as well as in breast cancer metastasis. We have demonstrated previously that β-arrestin2 functions to attenuate CXCR4-mediated G protein activation and to enhance CXCR4 internalization. Here we show further that the expression of β-arrestin2 in both HeLa and human embryonic kidney 293 cells significantly enhances the chemotactic efficacy of stromal cell-derived factor 1α, the specific agonist of CXCR4, whereas the suppression of β-arrestin2 endogenous expression by antisense or RNA-mediated interference technology considerably attenuates stromal cell-derived factor 1α-induced cell migration. Expression of β-arrestin2 also augmented chemokine receptor CCR5-mediated but not epidermal growth factor receptor-mediated chemotaxis, indicating the specific effect of β-arrestin2. Further analysis reveals that expression of β-arrestin2 strengthened CXCR4-mediated activation of both p38 MAPK and ERK, and the suppression of β-arrestin2 expression blocked the activation of two kinases. Interestingly, inhibition of p38 MAPK activation (but not ERK activation) by its inhibitors or by expression of a dominant-negative mutant of p38 MAPK effectively blocked the chemotactic effect of β-arrestin2. Expression of a dominant-negative mutant of ASK1 also exerted the similar blocking effect. The results of our study suggest that β-arrestin2 can function not only as a regulator of CXCR4 signaling but also as a mediator of stromal cell-derived factor 1α-induced chemotaxis and that this activity probably occurs via the ASK1/p38 MAPK pathway.

Abstract 256: Ablation of 14-3-3 Protein Exacerbates Doxorubicin Induced Cardiomyopathy: Role of Apoptosis Signal Regulating Kinase-1

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Vengadeshprabhu Karuppagounder ◽  
Somasundaram Arumugam ◽  
Remya Sreedhar ◽  
Vijayasree V Giridharan ◽  
Rejina Afrin ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Injury ◽  
High Mobility ◽  
Left Ventricular ◽  
Dominant Negative ◽  
Checkpoint Control ◽  
Specific Expression ◽  
Myocardial Apoptosis ◽  
Fractional Shortening

Background: 14-3-3η family members are dimeric phosphoserine-binding proteins that participate in signal transduction and checkpoint control pathways. Anthracycline anticancer drug doxorubicin (Dox) can induce cardiotoxicity, which is believed to be based on inflammatory or oxidative injury. However, the role of 14-3-3η is not clear in Dox induced cardiac injury. We examined the role of 14-3-3η protein and apoptosis signal-regulating kinase-1 (Ask1) and inflammatory signaling by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3η protein mutant (DN 14-3-3) in Dox induced cardiac injury. Methods: Cardiac dysfunction was induced by a single injection of Dox into wild-type (WT) and DN 14-3-3η mice. By the end of the study, echocardiography was performed to assess the cardiac function. The heart tissues were used for histopathology and western blotting. Results: Left ventricular (LV) fractional shortening and ejection fraction were dramatically decreased in DN 14-3-3η mice, when compared to WT mice after Dox injection. Inactivation of 14-3-3η protein significantly increased Dox induced mortality. Significant Ask1 activation in DN 14-3-3η after Dox injection was evidenced by pronounced de-phosphorylation at Ser-967 and intense immunofluorescence observed LV sections. Marked increase in myocardial apoptosis, cardiac hypertrophy, and fibrosis were observed with a corresponding up-regulation of proinflammatory factors and cytokine expression in DN 14-3-3η mice after Dox injection. Furthermore cardiac expression of high mobility group box (HMGB)1 and its cascade protein expressions were significantly up-regulated in DN 14-3-3η mice compared to WT mice after Dox injection. Conclusion: Taken together, these findings suggest that depletion of 14-3-3η protein causes reduce survival rate in mice with cardiac dysfunction, presumably via activation of downstream Ask1 signaling pathways. This may provide a novel therapeutic strategy against Dox-induced cardiac injury by regulating Ask1 signaling.

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

2008 ◽  
Vol 56 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Ewa Jablonska ◽  
Wioletta Ratajczak ◽  
Jakub Jablonski
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Inos Expression ◽  
Human Leukocytes ◽  
P38 Mapk Pathway

Inhibition of the water channel aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Montiel ◽  
R Bella ◽  
L Michel ◽  
E Robinson ◽  
J.C Jonas ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Myocyte ◽  
Water Channel ◽  
Transmembrane Transport ◽  
Funding Source ◽  
Water Pore

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

Phosphatidylinositol 3-kinase mediates integrin-dependent NF-(κ)B and MAPK activation through separate signaling pathways

2001 ◽  
Vol 114 (8) ◽  
pp. 1579-1589 ◽  
Author(s):  
M. Reyes-Reyes ◽  
N. Mora ◽  
A. Zentella ◽  
C. Rosales
Keyword(s):  
Signaling Pathways ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Dependent Manner ◽  
Monocytic Leukemia ◽  
Monocytic Cells ◽  
Mapk Activation

Integrin-mediated signals play an important but poorly understood role in regulating many leukocyte functions. In monocytes and monocytic leukemia cells, (β)1 integrin-mediated adhesion results in a strong induction of immediate-early genes that are important in inflammation. To investigate the signaling pathways from integrins in monocytic cells, THP-1 cells were stimulated via (β)1 integrins by binding to fibronectin and by crosslinking the integrins with specific monoclonal antibodies. The involvement of MAPK and PI 3-K on nuclear factor (κ)B (NF-(κ)B) activation was then analyzed. We found that integrins activated both NF-(κ)B and MAPK in a PI 3-K-dependent manner, as wortmannin and LY294002 blocked these responses. However, the specific MEK inhibitor PD98059 did not prevent integrin-mediated NF-(κ)B activation. In contrast, a dominant negative mutant of Rac completely prevented NF-(κ)B activation, but it did not affect MAPK activation. These results indicate that integrin signaling to NF-(κ)B is not mediated by the MAPK pathway, but rather by the small GTPase Rac. In addition, a dominant negative form of Ρ augmented NF-(κ)B activation and blocked MAPK activation, implying that these two pathways are in competition with each other. These data suggest that integrins activate different signaling pathways in monocytic cells. One uses PI 3-K and Rac to activate NF-(κ)B, while the other uses PI 3-K, MEK, and MAPK to activate other nuclear factors, such as Elk-1.

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Daniel N Meijles ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Braf Mutations ◽  
Gene Markers ◽  
Lv Mass ◽  
Cardiac Volumes

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

Acute adenosine preconditioning is mediated by p38 MAPK activation in discrete subcellular compartments

2005 ◽  
Vol 288 (3) ◽  
pp. H1359-H1366 ◽  
Author(s):  
Cherry Ballard-Croft ◽  
Gentian Kristo ◽  
Yukihiro Yoshimura ◽  
Easton Reid ◽  
Byron J. Keith ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Adenosine Receptor ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fraction ◽  
Control Group ◽  
Mapk Activation ◽  
Subcellular Compartments ◽  
Sb 203580

Although acute adenosine preconditioning (PC) is well established, the signaling pathways mediating this cardioprotection remain unclear. Because adenosine receptor agonists activate p38 MAPK and this kinase has been implicated in ischemic and pharmacological PC, the purpose of this study was to determine the role of p38 MAPK in acute adenosine receptor PC. The role of p38 MAPK activation in discrete subcellular compartments during ischemia-reperfusion was also determined. The following groups were used in an in vivo rat ischemia-reperfusion model: 1) control (10% DMSO iv), 2) the A1/A2a adenosine receptor AMP-579 (50 μg/kg iv), 3) AMP-579 + the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 μg/kg iv), 4) AMP-579 + the p38 MAPK inhibitor SB-203580 (1 mg/kg iv), and 5) SB-203580 alone. p38 MAPK activation was measured by Western blot analysis in cytosolic, mitochondrial, membrane, and nuclear/myofilament fractions obtained from hearts at preischemic, ischemic, and reperfusion time points. A significant reduction in infarct size was observed with AMP-579 PC, an effect blocked by DPCPX or SB-203580 pretreatment. AMP-579 treatment was associated with a significant increase in p38 MAPK activation in the nuclear/myofilament fraction before ischemia, whereas no activation of this kinase occurred during ischemia or reperfusion. In contrast, p38 MAPK was activated in the mitochondrial fraction by ischemia and in the cytosolic, mitochondrial, and membrane fractions by reperfusion in the control group. SB-203580 blocked the AMP-579-induced increase in phosphorylation of the downstream p38 substrate activating transcription factor-2. These results suggest a role for p38 MAPK activation in discrete subcellular compartments in acute adenosine A1 receptor PC.

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