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Am J Physiol Lung Cell Mol Physiol 283: L707-L716, 2002. First published May 17, 2002; doi:10.1152/ajplung.00024.2002
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Vol. 283, Issue 4, L707-L716, October 2002

Activation of multiple signaling modules is critical in angiotensin IV-induced lung endothelial cell proliferation

Yong D. Li1, Edward R. Block1,2, and Jawaharlal M. Patel1,2

1 Department of Medicine, University of Florida College of Medicine; and 2 Research Service, Malcom Randall Department of Veterans Affairs Medical Center, Gainesville, Florida 32608-1197

Signaling events involving angiotensin IV (ANG IV)-mediated pulmonary artery endothelial cell (PAEC) proliferation were examined. ANG IV significantly increased upstream phosphatidylinositide (PI) 3-kinase (PI3K), PI-dependent kinase-1 (PDK-1), extracellular signal-related kinases (ERK1/2), and protein kinase B-alpha /Akt (PKB-alpha ) activities, as well as downstream p70 ribosomal S6 kinase (p70S6K) activities and/or phosphorylation of these proteins. ANG IV also significantly increased 5-bromo-2'-deoxy-uridine incorporation into newly synthesized DNA in a concentration- and time-dependent manner. Pretreatment of cells with wortmannin and LY-294002, inhibitors of PI3K, or rapamycin, an inhibitor of the mammalian target of rapamycin kinase and p70S6K, diminished the ANG IV-mediated activation of PDK-1 and PKB-alpha as well as phosphorylation of p70S6K. Although an inhibitor of mitogen-activated protein kinase kinase, PD-98059, but not rapamycin, blocked ANG IV-induced phosphorylation of ERK1/2, both PD-98059 and rapamycin independently caused partial reduction in ANG IV-mediated cell proliferation. However, simultaneous treatment with PD-98059 and rapamycin resulted in total inhibition of ANG IV-induced cell proliferation. These results demonstrate that ANG IV-induced DNA synthesis is regulated in a coordinated fashion involving multiple signaling modules in PAEC.

p70 S6 kinase; protein kinase B; phosphatidylinositol 3-kinase


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