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J Appl Physiol (October 22, 2004). doi:10.1152/japplphysiol.00715.2004
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Submitted on July 9, 2004
Accepted on October 18, 2004

Activation of Phosphatidylinositol 3-Kinase, Akt and Mammalian Target of Rapamycin (mTOR) Is Necessary for Hypoxia-Induced Pulmonary Artery Adventitial Fibroblast Proliferation

Evgenia V Gerasimovskaya1, Doug A Tucker1, and Kurt R Stenmark1*

1 Developmental Lung Biology Laboratory, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: Kurt.Stenmark{at}UCHSC.edu.

In contrast to cell types in which exposure to hypoxia causes a general reduction of metabolic activity, a remarkable feature of pulmonary artery adventitial fibroblasts is their ability to proliferate in response to hypoxia. Previous studies have suggested that ERK1/2, phosphatidylinositol-3' kinase (PI3K), Akt, and mammalian Target of Rapamycin (mTOR) are activated by hypoxia and play a role in a variety of cell responses. However, the pathways involved in mediating hypoxia-induced proliferation are largely unknown. Using pharmacologic inhibitors, we established that PI3K/Akt, mTOR/p70S6K, and EKR1/2 signaling pathways play a critical role in hypoxia-induced adventitial fibroblast proliferation. We found that exposure of serum-starved fibroblasts to 3% O2 resulted in a time-dependent activation of PI3K and transient phosphorylation of Akt. However, activation PI3K was not required for activation of ERK1/2, implying a parallel involvement of these pathways in the proliferative response of fibroblasts to hypoxia. We found that hypoxia induced significant increases in mTOR, p70S6K, 4E-BP1, and S6 ribosomal protein phosphorylation, as well as dramatic increases in p70S6K activity. The activation of p70S6K/S6 pathway was sensitive to inhibition by rapamycin and LY294002, indicating that mTOR and PI3K/Akt are upstream signaling regulators. However, the magnitude of hypoxia-induced p70S6K activity and phosphorylation suggests involvement of additional signaling pathways. Thus, our data demonstrate that hypoxia-induced adventitial fibroblast proliferation requires activation and interaction of PI3K, Akt, mTOR, p70S6K, and ERK1/2 and provide evidence for hypoxic regulation of protein translational pathways in cells exhibiting the capability to proliferate under hypoxic conditions.




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