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(Circulation Research. 2005;96:164.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Cytokine-Stimulated GTP Cyclohydrolase I Expression in Endothelial Cells Requires Coordinated Activation of Nuclear Factor-B and Stat1/Stat3

Annong Huang, Ying-Yi Zhang, Kai Chen, Kazuyuki Hatakeyama, John F. Keaney, Jr

From the Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute (A.H., Y.Z., K.C., J.F.K.Jr.), Boston University School of Medicine, Boston, Mass; and Department of Surgery (K.H.), University of Pittsburgh, Pa.

Correspondence to John F. Keaney Jr, Boston University School of Medicine, Whitaker Cardiovascular Institute, 715 Albany St, Rm W507, Boston, MA 02118. E-mail jkeaney{at}bu.edu

Endothelial production of nitric oxide (NO) is dependent on adequate cellular levels of tetrahydrobiopterin (BH₄), an important cofactor for the nitric oxide synthases. Vascular diseases are often characterized by vessel wall inflammation and cytokine treatment of endothelial cells increases BH₄ levels, in part through the induction of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for BH₄ biosynthesis. However, the molecular mechanisms of cytokine-mediated GTPCH I induction in the endothelium are not entirely clear. We sought to investigate the signaling pathways whereby cytokines induce GTPCH I expression in human umbilical vein endothelial cells (HUVECs). Interferon- (IFN-) induced endothelial cell GTPCH I protein and BH₄ modestly, whereas high-level induction required combinations of IFN- and tumor necrosis factor- (TNF-). In the presence of IFN-, TNF- increased GTPCH I mRNA in a manner dependent on nuclear factor-B (NF-B), as this effect was abrogated by overexpression of a dominant-negative IB construct. HUVEC IFN- treatment resulted in signal transducer and activator of transcription 1 (Stat1) activation and DNA binding in a Jak2-dependent manner, as this was inhibited by AG490. Conversely, overexpression of Jak2 effectively substituted for IFN- in supporting TNF-–mediated GTPCH I induction. The role of IFN- was also Stat1-dependent as Stat1-null cells exhibited no GTPCH I induction in response to cytokines. However, Stat1 activation with oncostatin M failed to support TNF-–mediated GTPCH I induction because of concomitant Stat3 activation. Consistent with this notion, siRNA-mediated Stat3 gene silencing allowed oncostatin M to substitute for IFN- in this system. These data implicate both NF-B and Stat1 in endothelial cell cytokine-stimulated GTPCH I induction and highlight the role of Stat3 in modulating Stat1-supported gene transcription. Thus, IFN- and TNF- exert distinct but cooperative roles for BH₄ biosynthesis in endothelium that may have important implications for vascular function during vascular inflammation.

Key Words: biopterin • endothelium • inflammation • cytokines • signal transducers and activators of transcription • nuclear factor-B

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