Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Taniyama, Yoshihiro; Ushio‐Fukai, Masuko; Hitomi, Hirofumi; Ročić, Petra; Kingsley, Michael; Pfahnl, Chun L; Weber, David S.; Alexander, R. Wayne; Griendling, Kathy K.

doi:10.1152/ajpcell.00439.2003

Cited by 113 publications

(94 citation statements)

References 28 publications

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“…kinase activity. This is consistent with previous studies in smooth muscle and mesenchymal cells suggesting a relationship between p38 MAP kinase and downstream Akt activation (45), including a recent report that p38 MAP kinase and its downstream effector MAPKAP-2 can mediate Akt activation (46). A separate study, also in muscle cells, demonstrated that Akt serine 473 is a substrate for MAPKAP-2 phosphorylation (31).…”

Section: Fig 6 Ezrin Activation After Initiation Of Nasupporting

confidence: 92%

Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Shiue

Musch

Wang

et al. 2005

Journal of Biological Chemistry

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Initiation of Na؉ -glucose cotransport in intestinal absorptive epithelia causes NHE3 to be translocated to the apical plasma membrane, leading to cytoplasmic alkalinization. We reported recently that this NHE3 translocation requires ezrin phosphorylation. However, the kinase that phosphorylates ezrin in this process has not been identified. Because Akt has also been implicated in NHE3 translocation, we investigated the hypothesis that Akt phosphorylates ezrin. After initiation of Na ؉ -glucose cotransport, Akt is activated with kinetics that parallel those of ezrin phosphorylation. Inhibition of p38 MAP kinase, which blocks ezrin phosphorylation, also prevents Akt activation. Purified Akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an ATP-dependent manner. This in vitro phosphorylation can be prevented by Akt inhibitors. In intact cells, inhibition of either phosphoinositide 3-kinase, an upstream regulator of Akt, or inhibition of Akt itself using inhibitors validated in vitro prevents ezrin phosphorylation after initiation of Na ؉ -glucose cotransport. Specific small interfering RNA knockdown of Akt2 prevented ezrin phosphorylation in intact cells. Pharmacological Akt inhibition or Akt2 knockdown also prevented NHE3 translocation and activation after initiation of Na ؉ -glucose cotransport, confirming the functional role of Akt2. These studies therefore identify Akt2 as a critical kinase that regulates ezrin phosphorylation and activation. This Akt2-dependent ezrin phosphorylation leads to NHE3 translocation and activation.

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Section: Fig 6 Ezrin Activation After Initiation Of Nasupporting

confidence: 92%

Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Shiue

Musch

Wang

et al. 2005

Journal of Biological Chemistry

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“…This complex is necessary for Akt phosphorylation and activation in response to certain stimuli, such as angiotensin II stimulation, and for protecting neutrophils from apoptosis (37)(38)(39)(40). As shown in Figure 7A, p38 was activated in response to tunicamycin and thapsigargin treatment.…”

Section: Macrophage P38α Deficiency Leads To Enhanced Macrophage Apopmentioning

confidence: 96%

Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice

Seimon¹,

Wang²,

Han³

et al. 2009

J. Clin. Invest.

113

127

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ER stress occurs in macrophage-rich areas of advanced atherosclerotic lesions and contributes to macrophage apoptosis and subsequent plaque necrosis. Therefore, signaling pathways that alter ER stress-induced apoptosis may affect advanced atherosclerosis. Here we placed Apoe -/-mice deficient in macrophage p38α MAPK on a Western diet and found that they had a marked increase in macrophage apoptosis and plaque necrosis. The macrophage p38α-deficient lesions also exhibited a significant reduction in collagen content and a marked thinning of the fibrous cap, which suggests that plaque progression was advanced in these mice. Consistent with our in vivo data, we found that ER stress-induced apoptosis in cultured primary mouse macrophages was markedly accelerated under conditions of p38 inhibition. Pharmacological inhibition or genetic ablation of p38 suppressed activation of Akt in cultured macrophages and in atherosclerotic lesions. In addition, inhibition of Akt enhanced ER stress-induced macrophage apoptosis, and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stress-induced apoptosis that occurred with p38 inhibition in cultured cells. Our results demonstrate that p38α MAPK may play a critical role in suppressing ER stress-induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo.

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“…Inhibition of p38 MAPK has been shown to improve endothelial function and decrease Ang II-dependent vasoconstriction. [11][12][13] Ang II activates the p38 MAPK through increased ROS generation in vitro. 14,15 p38 MAPK activation is thought to be a calmodulin/calcium independent pathway of Ang II-mediated vasoconstriction.…”

mentioning

confidence: 99%

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

et al. 2014

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Abstract-Apolipoprotein E-deficient (apoE(−/−)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)(1-7) treatment ameliorates endothelial dysfunction in apoE(−/−) mice. However, the mechanism of Ang(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang(1-7) function, we used apoE(−/−) and wildtype mice fed on Western diet that were treated via osmotic minipumps either with Ang(1-7) (82 μg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(−/−) compared with wildtype mice. This apoE(−/−)specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC 20 ), causing renal vasoconstriction. Here, we provide evidence that chronic Ang(1-7) treatment attenuated the renal pressor response to Ang II in apoE(−/−) mice to wildtype levels. Ang(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogenactivated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogenactivated protein kinase inhibitor SB203580 (5 μmol/L), causing a reduced renal pressor response to Ang II in apoE(−/−) but not in apoE(−/−) mice treated with Ang(1-7). Moreover, Ang(1-7) treatment had no effect in Mas(−/−)/apoE(−/−) doubleknockout mice confirming the specificity of Ang (1-

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Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Cited by 113 publications

References 28 publications

Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

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