Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: Evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia

Masaya Tanno, Rekha Bassi, Diana A. Gorog, Adrian T. Saurin, Jie Jiang, Richard J. Heads, Jody L. Martin, Roger J. Davis, Richard A. Flavell, Michael S. Marber

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Abstract

The ischemic activation of p38α mitogen-activated protein kinase (p38α-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/- munne heart should be protected during ischemia. In retrogradely perfused mkk3-/- and mkk3 +/+ mouse hearts subjected to 30 minutes of global ischemia and 120 minutes of reperfusion, infarction/risk volume was similar (50±5 versus 51±4, P=0.93, respectively), as was intraischemic p38-MAPK phosphorylation (10 minutes ischemia as percent basal, 608±224 versus 384±104, P=0.43, respectively). This occurred despite undetectable activation of MKK3/6 in mkk3-/- hearts. However, tumor necrosis factor (TNF)-induced p38-MAPK phosphorylation was markedly diminished in mkk3-/- vs mkk3+/+ hearts (percent basal, 127±23 versus 540±267, respectively, P=0.04), suggesting an MKK-independent activation mechanism by ischemia. Hence, we examined p38-MAPK activation by TAB1-associated autophosphorylation. In wild-type mice and mkk3-/- mice, the p38-MAPK catalytic site inhibitor SB203580 (1 μmol/L) diminished phosphorylation during ischemia versus control (10 minutes ischemia as percent basal, 143±2 versus 436±96, P=0.003, and 122±25 versus 623±176, P=0.05, respectively) and reduced infarction volume (infarction/risk volume, 57±5 versus 36±3, P<0.001, and 50±5 versus 29±3, P=0.003, respectively) but did not alter TNF-induced activation, although in homogenates of ischemic hearts but not TNF-exposed hearts, p38-MAPK was associated with TAB1. Furthermore, adenovirally expressed wild-type and drug-resistant p38α-MAPK, lacking the SB203580 binding site, was phosphorylated when H9c2 myoblasts were subjected to simulated ischemia. However, SB203580 (1 μmol/L) did not prevent the phosphorylation of resistant p38α-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.

Original languageEnglish
Pages (from-to)254-261
Number of pages8
JournalCirculation Research
Volume93
Issue number3
Early online date26 Jun 2003
DOIs
Publication statusPublished - 8 Aug 2003

Fingerprint

p38 Mitogen-Activated Protein Kinases
Myocardial Ischemia
Ischemia
Wounds and Injuries
Phosphorylation
Infarction
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinase 10
Myoblasts
Reperfusion
Catalytic Domain
Binding Sites

Keywords

  • Ischemic preconditioning
  • Mitogen-activated protein kinase kinase 3
  • Myocardial infarction
  • p38 mitogen-activated protein kinase
  • TAB1

Cite this

Tanno, Masaya ; Bassi, Rekha ; Gorog, Diana A. ; Saurin, Adrian T. ; Jiang, Jie ; Heads, Richard J. ; Martin, Jody L. ; Davis, Roger J. ; Flavell, Richard A. ; Marber, Michael S. / Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation : Evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia. In: Circulation Research. 2003 ; Vol. 93, No. 3. pp. 254-261.
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abstract = "The ischemic activation of p38α mitogen-activated protein kinase (p38α-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/- munne heart should be protected during ischemia. In retrogradely perfused mkk3-/- and mkk3 +/+ mouse hearts subjected to 30 minutes of global ischemia and 120 minutes of reperfusion, infarction/risk volume was similar (50±5 versus 51±4, P=0.93, respectively), as was intraischemic p38-MAPK phosphorylation (10 minutes ischemia as percent basal, 608±224 versus 384±104, P=0.43, respectively). This occurred despite undetectable activation of MKK3/6 in mkk3-/- hearts. However, tumor necrosis factor (TNF)-induced p38-MAPK phosphorylation was markedly diminished in mkk3-/- vs mkk3+/+ hearts (percent basal, 127±23 versus 540±267, respectively, P=0.04), suggesting an MKK-independent activation mechanism by ischemia. Hence, we examined p38-MAPK activation by TAB1-associated autophosphorylation. In wild-type mice and mkk3-/- mice, the p38-MAPK catalytic site inhibitor SB203580 (1 μmol/L) diminished phosphorylation during ischemia versus control (10 minutes ischemia as percent basal, 143±2 versus 436±96, P=0.003, and 122±25 versus 623±176, P=0.05, respectively) and reduced infarction volume (infarction/risk volume, 57±5 versus 36±3, P<0.001, and 50±5 versus 29±3, P=0.003, respectively) but did not alter TNF-induced activation, although in homogenates of ischemic hearts but not TNF-exposed hearts, p38-MAPK was associated with TAB1. Furthermore, adenovirally expressed wild-type and drug-resistant p38α-MAPK, lacking the SB203580 binding site, was phosphorylated when H9c2 myoblasts were subjected to simulated ischemia. However, SB203580 (1 μmol/L) did not prevent the phosphorylation of resistant p38α-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.",
keywords = "Ischemic preconditioning, Mitogen-activated protein kinase kinase 3, Myocardial infarction, p38 mitogen-activated protein kinase, TAB1",
author = "Masaya Tanno and Rekha Bassi and Gorog, {Diana A.} and Saurin, {Adrian T.} and Jie Jiang and Heads, {Richard J.} and Martin, {Jody L.} and Davis, {Roger J.} and Flavell, {Richard A.} and Marber, {Michael S.}",
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Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation : Evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia. / Tanno, Masaya; Bassi, Rekha; Gorog, Diana A.; Saurin, Adrian T.; Jiang, Jie; Heads, Richard J.; Martin, Jody L.; Davis, Roger J.; Flavell, Richard A.; Marber, Michael S.

In: Circulation Research, Vol. 93, No. 3, 08.08.2003, p. 254-261.

Research output: Contribution to journalArticle

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T1 - Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation

T2 - Evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia

AU - Tanno, Masaya

AU - Bassi, Rekha

AU - Gorog, Diana A.

AU - Saurin, Adrian T.

AU - Jiang, Jie

AU - Heads, Richard J.

AU - Martin, Jody L.

AU - Davis, Roger J.

AU - Flavell, Richard A.

AU - Marber, Michael S.

PY - 2003/8/8

Y1 - 2003/8/8

N2 - The ischemic activation of p38α mitogen-activated protein kinase (p38α-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/- munne heart should be protected during ischemia. In retrogradely perfused mkk3-/- and mkk3 +/+ mouse hearts subjected to 30 minutes of global ischemia and 120 minutes of reperfusion, infarction/risk volume was similar (50±5 versus 51±4, P=0.93, respectively), as was intraischemic p38-MAPK phosphorylation (10 minutes ischemia as percent basal, 608±224 versus 384±104, P=0.43, respectively). This occurred despite undetectable activation of MKK3/6 in mkk3-/- hearts. However, tumor necrosis factor (TNF)-induced p38-MAPK phosphorylation was markedly diminished in mkk3-/- vs mkk3+/+ hearts (percent basal, 127±23 versus 540±267, respectively, P=0.04), suggesting an MKK-independent activation mechanism by ischemia. Hence, we examined p38-MAPK activation by TAB1-associated autophosphorylation. In wild-type mice and mkk3-/- mice, the p38-MAPK catalytic site inhibitor SB203580 (1 μmol/L) diminished phosphorylation during ischemia versus control (10 minutes ischemia as percent basal, 143±2 versus 436±96, P=0.003, and 122±25 versus 623±176, P=0.05, respectively) and reduced infarction volume (infarction/risk volume, 57±5 versus 36±3, P<0.001, and 50±5 versus 29±3, P=0.003, respectively) but did not alter TNF-induced activation, although in homogenates of ischemic hearts but not TNF-exposed hearts, p38-MAPK was associated with TAB1. Furthermore, adenovirally expressed wild-type and drug-resistant p38α-MAPK, lacking the SB203580 binding site, was phosphorylated when H9c2 myoblasts were subjected to simulated ischemia. However, SB203580 (1 μmol/L) did not prevent the phosphorylation of resistant p38α-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.

AB - The ischemic activation of p38α mitogen-activated protein kinase (p38α-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/- munne heart should be protected during ischemia. In retrogradely perfused mkk3-/- and mkk3 +/+ mouse hearts subjected to 30 minutes of global ischemia and 120 minutes of reperfusion, infarction/risk volume was similar (50±5 versus 51±4, P=0.93, respectively), as was intraischemic p38-MAPK phosphorylation (10 minutes ischemia as percent basal, 608±224 versus 384±104, P=0.43, respectively). This occurred despite undetectable activation of MKK3/6 in mkk3-/- hearts. However, tumor necrosis factor (TNF)-induced p38-MAPK phosphorylation was markedly diminished in mkk3-/- vs mkk3+/+ hearts (percent basal, 127±23 versus 540±267, respectively, P=0.04), suggesting an MKK-independent activation mechanism by ischemia. Hence, we examined p38-MAPK activation by TAB1-associated autophosphorylation. In wild-type mice and mkk3-/- mice, the p38-MAPK catalytic site inhibitor SB203580 (1 μmol/L) diminished phosphorylation during ischemia versus control (10 minutes ischemia as percent basal, 143±2 versus 436±96, P=0.003, and 122±25 versus 623±176, P=0.05, respectively) and reduced infarction volume (infarction/risk volume, 57±5 versus 36±3, P<0.001, and 50±5 versus 29±3, P=0.003, respectively) but did not alter TNF-induced activation, although in homogenates of ischemic hearts but not TNF-exposed hearts, p38-MAPK was associated with TAB1. Furthermore, adenovirally expressed wild-type and drug-resistant p38α-MAPK, lacking the SB203580 binding site, was phosphorylated when H9c2 myoblasts were subjected to simulated ischemia. However, SB203580 (1 μmol/L) did not prevent the phosphorylation of resistant p38α-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.

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