Abstract 68: p38 MAP Kinase Regulates Chamber Specific Postnatal Remodelling of Cardiac Ventricles

Background: Left ventricle (LV) and right ventricle (RV) in mouse heart undergo dramatically different chamber-specific remodeling after birth, leading to rapid increase in LV vs. RV chamber size. However, the underlying regulatory mechanism mediating chamber specific remodeling process remains enigmatic. Results and Methods: In neonatal mouse heart, p38 MAP kinase activity is dynamically activated in a chamber specific manner. p38 activity is specifically elevated in RV comparing to LV at E18.5, postnatal day 3 (P3) and P7 stages whereas p38 activity is lower in both ventricles at P0 and P1. In mouse heart with cardiomyocyte specific-knockout of p38α and β (p38ab-cdKO), total p38 activity was diminished in both chambers. The p38ab-cdKO mice had significant neonatal lethality associated with RV specific chamber enlargement and significant increase in both RV wall thickness (RVW) and inner diameter of RV (RVID) as early as P3. Interestingly, p38 inactivation suppressed myocyte apoptotic activity specifically in RV while increased RV myocyte proliferation and hypertrophy during neonatal period. Unexpectedly, RNA-seq results implicated Xbp1 mediated transcriptional regulation significantly contributing to p38 dependent transcriptome reprogramming in RV. Indeed, IRE1α expression in neonatal cardiomyocyte is sufficient to induce proliferation in vitro. Furthermore, knockdown of Xbp1 blunted p38 inhibition-induced myocyte proliferation, suggesting that IRE1a/Xbp1 mediate p38 signaling in neonatal myocyte proliferation. Conclusion: Chamber-specific remodeling in neonatal heart involves temporally regulated and RV specific p38 MAP kinase activity. RV specific myocyte proliferation and hypertrophy concurrent with RV specific programmed myocyte death is orchestrated by two innate stress-response pathways, p38 and Xbp1.

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Abstract 287: Chamber Specific Function of p38 MAP Kinases in Right Ventricle Development, Hypertrophy, and Dysfunction

Circulation Research ◽

10.1161/res.115.suppl_1.287 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Tomohiro Yokota ◽

Vincent Ren ◽

Yibin Wang

Keyword(s):

Right Ventricle ◽

Map Kinase ◽

Map Kinases ◽

Wild Type Mouse ◽

Left Ventricular ◽

P38 Map Kinase ◽

Wild Type ◽

Apoptotic Activity ◽

The Right ◽

Myocyte Proliferation

Background: Postnatal heart maturation is a well orchestrated process involving chamber specific changes in myocyte proliferation and growth. While the left ventricle undergoes significant growth, the right ventricle regresses relative to the left in terms of both myocyte number and size. While much attention has been focused on the left ventricular myocyte proliferation and hypertrophy, right ventricle specific changes are poorly studied. p38 MAP kinase is a well established signaling pathway for stress response and also plays an important role in cell differentiation, viability and proliferation. Its role in chamber specific postnatal heart maturation, however, has not been demonstrated Results and Methods: We observed RV specific induction of myocyte apoptosis and suppression of myocyte proliferation in neonatal hearts, coinciding with a transient induction of p38 activity significantly higher in the RV relative to the LV at P3 and P7 wild-type mouse hearts. In cardiomyocyte specific p38 MAP kinase alpha&beta double KO (p38ab cdKO) mice, echocardiographic and histological analyses revealed RV specific chamber enlargement and dysfunction associated with significant postnatal lethality. Apoptotic activity in the RV was suppressed at P1 and myocyte proliferation and hypertrophy were significantly elevated at P3 and P7 in the p38ab cdKO hearts compared to the wild-type. In contrast, no differences were observed in the LV between the p38ab cdKO and wild-type. Consequently, the surviving p38ab cdKO mice showed significant and RV specific enlargement and dysfunction, leading to eventual RV failure and pulmonary hypertension. Conclusion: p38 a&b MAP kinases are essential to RV specific maturation in postnatal hearts. p38ab cdKO mice represent a unique RV-specific hypertrophy and heart failure model for further studies.

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Differential Activation of Mitogen-Activated Protein Kinases in Experimental Mesangioproliferative Glomerulonephritis

Journal of the American Society of Nephrology ◽

10.1681/asn.v112232 ◽

2000 ◽

Vol 11 (2) ◽

pp. 232-240

Author(s):

DIRK BOKEMEYER ◽

TAMMO OSTENDORF ◽

UTA KUNTER ◽

MARION LINDEMANN ◽

HERBERT J. KRAMER ◽

...

Keyword(s):

Map Kinase ◽

Map Kinases ◽

Cellular Proliferation ◽

Kinase Activity ◽

P38 Map Kinase ◽

Cellular Growth ◽

Terminal Deoxynucleotidyl Transferase ◽

Maximal Increase

Abstract. Multiple extracellular mitogens are involved in the pathogenesis of proliferative forms of glomerulonephritis (GN). In vitro studies demonstrate the pivotal role of mitogenactivated protein (MAP) kinases in the regulation of cellular proliferation. This study was conducted to examine whether these kinases, as a convergence point of mitogenic stimuli, are activated in mesangioproliferative GN in vivo. Therefore, anti-Thy1 GN was induced in rats using a monoclonal anti-Thy1.1 antibody (OX-7). Whole cortical tissue as well as isolated glomeruli were examined at different time points using kinase activity assays and Western blot analysis. A maximal increase in the number of glomerular mitotic figures (9.7-fold) was demonstrated 6 d after injection of the anti-Thy1.1 antibody. In parallel with this finding, a significant increase in cortical, and more dramatically glomerular, activity of extracellular signal-regulated kinase (ERK) was detected. Maximal activation of ERK was detectable on day 6. This activation of ERK was accompanied by an increase in the expression of MEK (MAP kinase/ERK kinase), the ERK-activating kinase. A marked induction of glomerular apoptosis at 2 h after injection of the anti-Thy1.1 antibody, which subsided subsequently, was demonstrated using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay as well as staining for single-stranded DNA. However, no significant activation of stress-activated protein kinase or p38 MAP kinase, both MAP kinases that are suggested to induce apoptosis and to inhibit cellular growth, was detectable at this early time point. Rather, on day 6 a dramatic decrease in the activity of p38 MAP kinase, which might have contributed to the overshooting glomerular cellular proliferation, was observed. Treatment of rats with heparin blunted glomerular proliferation as well as ERK activation and restored p38 MAP kinase activity. These observations point to ERK and p38 MAP kinase as putative mediators of the proliferative response in mesangioproliferative GN and suggest that upregulation of MEK is involved in the long-term regulation of ERK in vivo.

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Inhibition of the MAP kinase activity suppresses estrogen-induced breast tumor growth both in vitro and in vivo

International Journal of Oncology ◽

10.3892/ijo.30.4.971 ◽

2007 ◽

Author(s):

Kaladhar Reddy ◽

Selina Glaros

Keyword(s):

Tumor Growth ◽

Map Kinase ◽

Breast Tumor ◽

Kinase Activity

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Boswellia serrata oleo-gum-resin and β-boswellic acid inhibits HSV-1 infection in vitro through modulation of NF-кB and p38 MAP kinase signaling

Phytomedicine ◽

10.1016/j.phymed.2018.10.016 ◽

2018 ◽

Vol 51 ◽

pp. 94-103 ◽

Cited By ~ 11

Author(s):

Debayan Goswami ◽

Ananya Das Mahapatra ◽

Subhadip Banerjee ◽

Amit Kar ◽

Durbadal Ojha ◽

...

Keyword(s):

Map Kinase ◽

P38 Map Kinase ◽

Kinase Signaling ◽

Boswellic Acid ◽

Boswellia Serrata ◽

Map Kinase Signaling ◽

Hsv 1

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Differential role of cAMP, cGMP and Ca2+ and involvement of kinases and CBP-CREB-CRE pathway in regulation of arylalkylamine N-acetyltransferase 2 gene in the pineal organ of air-breathing catfish, Clarias gariepinus

10.21203/rs.3.rs-422474/v1 ◽

2021 ◽

Author(s):

Hijam Nonibala ◽

Braj Bansh Prasad Gupta

Keyword(s):

Gene Expression ◽

Map Kinase ◽

Gene Transcription ◽

Pineal Organ ◽

Clarias Gariepinus ◽

Specific Inhibitor ◽

P38 Map Kinase ◽

Camp And Cgmp

Abstract Transcription of arylalkylamine N-acetyltransferase 2 (aanat2) gene leads to formation of AANAT2 - the rate-limiting enzyme in melatonin synthesis pathway in photosensitive fish pineal organ. However, unlike in avian and mammalian pineal gland, there is practically no information on signal transduction pathway(s) involved in regulation of aanat2 gene transcription in the fish pineal organ. Therefore, we investigated the role of important molecular components of signalling via cAMP, cGMP, Ca2+ involving PKA, PKG, PKC, MeK and p38 MAP kinase as well as possible role of serine/threonine phosphatases, CREB and CBP using their specific inhibitors and/or activators in aanat2 gene transcription in the fish pineal organ maintained under in vitro culture-conditions. db-cAMP and db-cGMP stimulated the expression of aanat2 gene. db-cAMP- and cGMP-induced aanat2 gene expression was significantly reduced in the presence of H-89 (specific inhibitor of PKA), KT5823 (specific inhibitor of PKG), chelerythrine chloride (specific inhibitor of PKC), U0126 ethanolate (specific inhibitor of MeK) and SB 202190 monohydrochloride hydrate (specific inhibitor of p38 MAP kinase). Inhibitors of PP1 and PP2A significantly increased aanat2 gene expression as well as significantly reduced cAMP- and cGMP-induced gene transcription, while inhibitor of PP2B had no effect on aanat2 gene expression. Inhibitors of both CREB and CBP-CREB interaction completely blocked cAMP-induced aanat2 gene transcription. Based on these findings, we suggest that cAMP, cGMP and Ca2+ stimulate aanat2 gene transcription via PKA, PKG and PKC, respectively. Further, protein phosphatases and CBP-CREB-CRE pathway are actively involved in regulation of on aanat2 gene expression in the fish pineal organ.

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Co-culture with pig membrana granulosa cells modulates the activity of cdc2 and MAP kinase in maturing cattle oocytes

Zygote ◽

10.1017/s0967199400003166 ◽

1996 ◽

Vol 4 (3) ◽

pp. 247-256 ◽

Cited By ~ 18

Author(s):

Jan Motlík ◽

Peter Šutovský ◽

Jaroslav Kalous ◽

Michal Kubelka ◽

Jiří Moos ◽

...

Keyword(s):

Map Kinase ◽

Granulosa Cells ◽

Kinase Activity ◽

Histone H1 ◽

Meiotic Spindle ◽

Nuclear Envelope Breakdown ◽

Transmission Electron ◽

Initial Culture ◽

Metaphase I

SummaryBovine cumulus-enclosed oocytes, initially cultured up to diakinesis (8h of initial culture) or metaphase I (12h of initial culture), were subsequently co-cultured for 6 h in contact with pig membrana granulosa (PMG) cells and then assayed for histone H1 and MAP kinase activities. In addition, the phosphorylation state of ERK 1,2 proteins was determined by Western blotting. The alterations in nuclear envelope breakdown, meiotic spindle formation and the patterns of chromosome condensation were analysed by immunofluorescence and transmission electron microscopy. The diakinesis-stage oocytes (initially cultured for 8h) already possessed high histone H1 kinase and MAP kinase activities that were correlated with condensed and partially individualised chromosomes. The ERK 1 and most ERK 2 proteins were partly phosphorylated. Following the 6h co-culture of these oocytes with PMG a rapid decrease in MAP kinase activity and a slower decrease in histone H1 kinase occurred, as well as ERK 1 and ERK 2 dephosphorylation. Both kinase activities and ERK 1,2 phosphorylation were fully restored following the release of the oocytes from co-culture and a subsequent culture in the absence of PMG. Moreover, the clumped bivalents were reindividualised and 56% of these oocytes reached metaphase II after 20 h of culture without PMG. The metaphase I oocytes, initially cultured for 12 h, displayed a fusiform meiotic spindle and a metaphase array of chromosomal bivalents, accompanied by high levels of both histone H1 and MAP kinase activity. Co-culture of MI oocytes with PMG abolished the activity of both kinases and caused the dephosphorylation of ERK 1 and ERK 2. Furthermore, the spindle microtubules were depolymerised and the chromosomal bivalents clumped into a single mass. Neither of the protein kinase activities nor the meiotic spindle were restored following subsequent culture in the absence of PMG for up to 20 h. These observations indicate that under in vitro conditions membrana granulosa cells can cause a prompt decrease in histone H1 and MAP kinase activities, and metaphase I oocytes. While these events are fully reversible in late diakinesis oocytes, metaphase I oocytes did not complete maturation after release from co-culture.

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