CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120

SummaryWe investigated similarities in the signaling pathways elicited by the F2 isoprostane 8-iso-PGF2α and by low doses of U46619 to induce platelet activation. Both 0.01-0.1 µmol/L U46619 and 0.01-1 µmol/L 8-isoPGF2α triggered shape change and filopodia extension, as well as adhesion to immobilized fibrinogen of washed platelets. At these doses the two platelet agonists failed to trigger secretion and aggregation, which were however induced by higher doses of U46619 (0.1-1 µmol/L). SB203580 (1-10 µmol/L), a specific inhibitor of the p38 mitogen activated protein (MAP) kinase blunted platelet shape change and adhesion induced by 0.05-1 µmol/L 8-iso-PGF2α and by 0.01 µmol/L U46619. These platelet responses were also inhibited by 20 µmol/L cytochalasin D, an inhibitor of actin polymerization, and 50 µmol/L piceatannol, an inhibitor of the Syk tyrosine kinases. Both 8-iso-PGF2α and U46619-induced p38 MAP kinase phosphorylation in suspended platelets and this was inhibited by piceatannol, indicating that Syk activation occurs upstream p38 MAP kinase phosphorylation. These findings suggest that the signaling pathway triggered by both 8-iso-PGF2α and low concentrations of U46619 to induce platelet adhesion and shape change implicates Syk, the p38 MAP kinase, and actin polymerization.

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p38 MAP kinase inhibitor reverses stress-induced cardiac myocyte dysfunction

Journal of Applied Physiology ◽

10.1152/japplphysiol.00171.2004 ◽

2005 ◽

Vol 98 (1) ◽

pp. 77-82 ◽

Cited By ~ 6

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.

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p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

AJP Cell Physiology ◽

10.1152/ajpcell.00059.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. C1-C7 ◽

Cited By ~ 42

Author(s):

Hong Kan ◽

Zirong Xie ◽

Mitchell S. Finkel

Keyword(s):

Map Kinase ◽

Cardiac Myocytes ◽

Myocardial Dysfunction ◽

Negative Inotropic Effect ◽

P38 Map Kinase ◽

Neonatal Rat ◽

Inotropic Effect ◽

Kinase Activation ◽

Hiv Gp120 ◽

Sb 203580

Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca2+concentration ([Ca2+]i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased [Ca2+]iwithin 5 min and then depressed FS without a decrease in [Ca2+]iby 20–60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 μM) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 μM) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 μM) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.

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205 INVOLVEMENT OF P38 MAP KINASE PHOSPHORYLATION IN CHONDROCYTE APOPTOSIS INDUCED BY MECHANICAL STRESS AND HEAT STRESS

Osteoarthritis and Cartilage ◽

10.1016/s1063-4584(09)60227-2 ◽

2009 ◽

Vol 17 ◽

pp. S117

Author(s):

K. Takebe ◽

T. Nishiyama ◽

S. Hashimoto ◽

T. Fujishiro ◽

N. Kanzaki ◽

...

Keyword(s):

Heat Stress ◽

Map Kinase ◽

Mechanical Stress ◽

P38 Map Kinase ◽

Chondrocyte Apoptosis ◽

Kinase Phosphorylation

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P38 MAP Kinase Inhibitor Prevents Diastolic Dysfunction in Rats Following HIV gp120 Injection In vivo

Cardiovascular Toxicology ◽

10.1007/s12012-009-9047-1 ◽

2009 ◽

Vol 9 (3) ◽

pp. 142-150 ◽

Cited By ~ 10

Author(s):

Chalak Berzingi ◽

Fangping Chen ◽

Mitchell S. Finkel

Keyword(s):

Diastolic Dysfunction ◽

Map Kinase ◽

Kinase Inhibitor ◽

P38 Map Kinase ◽

Hiv Gp120

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Inhibition by adenylyl cyclase-cAMP system of ET-1-induced HSP27 in osteoblasts

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.6.e1260 ◽

2001 ◽

Vol 281 (6) ◽

pp. E1260-E1266 ◽

Cited By ~ 4

Author(s):

Daijiro Hatakeyama ◽

Osamu Kozawa ◽

Masayuki Niwa ◽

Hiroyuki Matsuno ◽

Kanefusa Kato ◽

...

Keyword(s):

Map Kinase ◽

Adenylyl Cyclase ◽

Mrna Level ◽

P38 Map Kinase ◽

Hsp 27 ◽

Kinase C ◽

Protein Map ◽

Mitogen Activated Protein ◽

Camp System ◽

Kinase Phosphorylation

We have previously reported that endothelin-1 (ET-1) stimulates heat shock protein (HSP) 27 induction in osteoblast-like MC3T3-E1 cells and that p38 mitogen-activated protein (MAP) kinase acts at a point downstream from protein kinase C (PKC) in HSP27 induction. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on ET-1-stimulated induction of HSP27 in MC3T3-E1 cells. Dibutyryl-cAMP (DBcAMP) dose dependently inhibited the HSP27 accumulation stimulated by ET-1. Forskolin and cholera toxin significantly suppressed the ET-1-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the ET-1-induced HSP27 accumulation. Forskolin reduced the p38 MAP kinase phosphorylation induced by ET-1 or 12- O-tetradecanoylphorbol-13-acetate (TPA). PGE1, an extracellular agonist that activates cAMP production, reduced the ET-1-induced HSP27 accumulation. In addition, the phosphorylation of p38 MAP kinase induced by ET-1 or TPA was suppressed by PGE1. Forskolin, DBcAMP, and PGE1suppressed the ET-1-stimulated increase in the mRNA level for HSP27. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in ET-1-stimulated HSP27 induction in osteoblasts and that the effect is exerted at the point between PKC and p38 MAP kinase in osteoblasts.

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Triptolide (PG-490) induces apoptosis of dendritic cells through sequential p38 MAP kinase phosphorylation and caspase 3 activation

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2004.04.201 ◽

2004 ◽

Vol 319 (3) ◽

pp. 980-986 ◽

Cited By ~ 52

Author(s):

Qiuyan Liu ◽

Taoyong Chen ◽

Huabiao Chen ◽

Minghui Zhang ◽

Nan Li ◽

...

Keyword(s):

Dendritic Cells ◽

Map Kinase ◽

Caspase 3 ◽

P38 Map Kinase ◽

Kinase Phosphorylation

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Gö6976 Protects Mesencephalic Neurons from Lipopolysaccharide-Elicited Death by Inhibiting p38 MAP Kinase Phosphorylation

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2002.tb04079.x ◽

2002 ◽

Vol 962 (1) ◽

pp. 347-359 ◽

Cited By ~ 9

Author(s):

GWANG-HO JEOHN ◽

CYNTHIA L. COOPER ◽

KYUNG-JIN JANG ◽

HYOUNG-CHUN KIM ◽

JAU-SHYONG HONG

Keyword(s):

Map Kinase ◽

P38 Map Kinase ◽

Kinase Phosphorylation

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Leishmania mexicana lipophosphoglycan activates ERK and p38 MAP kinase and induces production of proinflammatory cytokines in human macrophages through TLR2 and TLR4

Parasitology ◽

10.1017/s0031182013002187 ◽

2014 ◽

Vol 141 (6) ◽

pp. 788-800 ◽

Cited By ~ 23

Author(s):

A. ROJAS-BERNABÉ ◽

O. GARCIA-HERNÁNDEZ ◽

C. MALDONADO-BERNAL ◽

J. DELEGADO-DOMINGUEZ ◽

E. ORTEGA ◽

...

Keyword(s):

Map Kinase ◽

Map Kinases ◽

P38 Map Kinase ◽

Leishmania Mexicana ◽

Human Macrophages ◽

Parasite Survival ◽

Causative Agents ◽

Favourable Environment ◽

Kinase Phosphorylation ◽

Pro Inflammatory Cytokines

SUMMARYProtozoan parasites of genus Leishmania are the causative agents of leishmaniasis. Leishmania promastigotes primarily infect macrophages in the host, where they transform into amastigotes and multiply. Lipophosphoglycan (LPG), the most abundant surface molecule of the parasite, is a virulence determinant that regulates the host immune response. Promastigotes are able to modulate this effect through LPG, creating a favourable environment for parasite survival, although the mechanisms underlying this modulation remain unknown. We analysed the participation of TLR2 and TLR4 in the production of cytokines and explored the possible phosphorylation of ERK and/or p38 MAP kinase signalling cascades in human macrophages stimulated with Leishmania mexicana LPG. The results show that LPG induced the production of TNF-α, IL-1β, IL-12p40, IL-12p70 and IL-10 and led to phosphorylation of ERK and p38 MAP kinase. Specific inhibitors of ERK or p38 MAP kinases and mAbs against TLR2 and TLR4 reduced cytokine production and phosphorylation of both kinases. Our results suggest that L. mexicana LPG binds TLR2 and TLR4 receptors in human macrophages, leading to ERK and MAP kinase phosphorylation and production of pro-inflammatory cytokines.

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