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Circulation Research. 2005
Published online before print September 22, 2005, doi: 10.1161/01.RES.0000187458.77026.10
A more recent version of this article appeared on October 28, 2005
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Submitted on May 16, 2005
Revised on August 23, 2005
Accepted on September 9, 2005

AMP-Activated Protein Kinase Activates p38 Mitogen-Activated Protein Kinase by Increasing Its Recruitment to TAB1 in the Ischemic Heart

Ji Li ; Edward J. Miller ; Jun Ninomiya-Tsuji ; Raymond R. Russell III ; and Lawrence H. Young *

From the Section of Cardiovascular Medicine (J.L, E.J.M., R.R.R., L.H.Y.), Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn; and the Department of Environmental and Molecular Toxicology (J.N.-T.), North Carolina State University, Raleigh.

* To whom correspondence should be addressed. E-mail: lawrence.young{at}yale.edu.

AMP-activated protein kinase (AMPK) promotes glucose transport, maintains ATP stores, and prevents injury and apoptosis during ischemia. AMPK has several direct molecular targets in the heart but also may interact with other stress-signaling pathways. This study examined the role of AMPK in the activation of the p38 mitogen-activated protein kinase (MAPK). In isolated heart muscles, the AMPK activator 5-aminoimidazole-4-carboxy-amide-1-{beta}-D-ribofuranoside (AICAR) increased p38 activation. In AMPK-deficient mouse hearts, expressing a kinase-dead (KD) {alpha}2 catalytic subunit, p38 activation was markedly reduced during low-flow ischemia (2.3- versus 7-fold in wild-type hearts, P<0.01) and was similarly reduced during severe no-flow ischemia in KD hearts (P<0.01 versus ischemic wild type). Knockout of the p38 upstream kinase, MAPK kinase kinase (MKK3), did not affect ischemic activation of either AMPK or p38 in transgenic mkk3-/- mouse hearts. Ischemia increased p38 recruitment to transforming growth factor-{beta}-activated protein kinase 1-binding protein 1 (TAB1), a scaffold protein that promotes p38 autophosphorylation. Moreover, TAB1 was associated with the {alpha}2 catalytic subunit of AMPK. p38 recruitment to TAB1/AMPK complexes required AMPK activation and was absent in ischemic AMPK-deficient transgenic mouse hearts. The potential role of p38 in mediating the downstream action of AMPK to promote glucose transport was also assessed. The p38 inhibitor SB203580 partially inhibited both AICAR- and hypoxia-stimulated glucose uptake and glucose transporter 4 translocation. Activation of p38 by anisomycin also increased glucose transport in heart muscles. Thus, AMPK has an important role in promoting p38 activation in the ischemic heart by inducing p38 autophosphorylation through interaction with the scaffold protein TAB1.
Key words: ischemia • AMP-activated protein kinase • p38 mitogen-activated protein kinase • transforming growth factor-{beta}-activated protein kinase 1-binding protein 1 • glucose transport




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