Pathological conditions such as hypertension and hyper-glycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.
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页码:20995 / 21003
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Aguirre-Ghiso JA, 2003, CANCER RES, V63, P1684
机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Brancho, D
Tanaka, N
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Tanaka, N
Jaeschke, A
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Jaeschke, A
Ventura, JJ
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Ventura, JJ
Kelkar, N
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Kelkar, N
Tanaka, Y
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Tanaka, Y
Kyuuma, M
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Kyuuma, M
Takeshita, T
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Takeshita, T
Flavell, RA
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Flavell, RA
Davis, RJ
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Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USAUniv Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
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Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Camps, M
Nichols, A
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Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Nichols, A
Arkinstall, S
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Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Brancho, D
Tanaka, N
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Tanaka, N
Jaeschke, A
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Jaeschke, A
Ventura, JJ
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Ventura, JJ
Kelkar, N
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Kelkar, N
Tanaka, Y
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Tanaka, Y
Kyuuma, M
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Kyuuma, M
Takeshita, T
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Takeshita, T
Flavell, RA
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机构:Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
Flavell, RA
Davis, RJ
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Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USAUniv Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
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Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Camps, M
Nichols, A
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Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Nichols, A
Arkinstall, S
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Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland