Faculty Collaboration Database

Protein kinase B/Akt activates c-Jun NH(2)-terminal kinase by increasing NO production in response to shear stress. J Appl Physiol (1985) 2001 Oct;91(4):1574-81

Date

09/25/2001

Pubmed ID

11568138

DOI

10.1152/jappl.2001.91.4.1574

Scopus ID

2-s2.0-0034813334   85 Citations

Abstract

Laminar shear stress activates c-Jun NH(2)-terminal kinase (JNK) by the mechanisms involving both nitric oxide (NO) and phosphatidylinositide 3-kinase (PI3K). Because protein kinase B (Akt), a downstream effector of PI3K, has been shown to phosphorylate and activate endothelial NO synthase, we hypothesized that Akt regulates shear-dependent activation of JNK by stimulating NO production. Here, we examined the role of Akt in shear-dependent NO production and JNK activation by expressing a dominant negative Akt mutant (Akt(AA)) and a constitutively active mutant (Akt(Myr)) in bovine aortic endothelial cells (BAEC). As expected, pretreatment of BAEC with the PI3K inhibitor (wortmannin) prevented shear-dependent stimulation of Akt and NO production. Transient expression of Akt(AA) in BAEC by using a recombinant adenoviral construct inhibited the shear-dependent stimulation of NO production and JNK activation. However, transient expression of Akt(Myr) by using a recombinant adenoviral construct did not induce JNK activation. This is consistent with our previous finding that NO is required, but not sufficient on its own, to activate JNK in response to shear stress. These results and our previous findings strongly suggest that shear stress triggers activation of PI3K, Akt, and endothelial NO synthase, leading to production of NO, which (along with O(2-), which is also produced by shear) activates Ras-JNK pathway. The regulation of Akt, NO, and JNK by shear stress is likely to play a critical role in its antiatherogenic effects.

Author List

Go YM, Boo YC, Park H, Maland MC, Patel R, Pritchard KA Jr, Fujio Y, Walsh K, Darley-Usmar V, Jo H

Author

Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenoviridae Infections
Animals
Aorta, Thoracic
Blotting, Western
Cattle
Cells, Cultured
Endothelium, Vascular
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Nitric Oxide
Phosphatidylinositol 3-Kinases
Phosphorylation
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
Rheology