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, Jg. 93 (2003), Heft 3, S. 254-261
Online
academicJournal
- print, 33 ref
Zugriff:
The ischemic activation of p38a mitogen-activated protein kinase (p38a-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/-murine 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 TAB 1-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 p38a-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 p38a-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.
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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
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Autor/in / Beteiligte Person: | TANNO, Masaya ; BASSI, Rekha ; GOROG, Diana A ; SAURIN, Adrian T ; JIE, JIANG ; HEADS, Richard J ; MARTIN, Jody L ; DAVIS, Roger J ; FLAVELL, Richard A ; MARBER, Michael S |
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Zeitschrift: | Circulation research, Jg. 93 (2003), Heft 3, S. 254-261 |
Veröffentlichung: | Hagerstown, MD: Lippincott, 2003 |
Medientyp: | academicJournal |
Umfang: | print, 33 ref |
ISSN: | 0009-7330 (print) |
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