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1 Medicine/Cardiology, Emory University, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: kgriend{at}emory.edu.
Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the mitogen-activated protein kinases (MAPKs) and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases, or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38MAPK and its substrate MAPK-activated protein kinase-2 (MAPKAPK-2) mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38MAPK are constitutively associated, and remain so after angiotensin II stimulation. Inhibition of p38MAPK activity with SB203580 dose-dependently inhibits Akt phosphorylation on Ser473, but not Thr308. Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser473. These results suggest that the p38MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38MAPK. Through this mechanism, p38MAPK confers ROS-sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.
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