RT Journal Article
SR Electronic
T1 Selective HIF-1 Regulation under Nonhypoxic Conditions by the p42/p44 MAP Kinase Inhibitor, PD184161
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.108654
DO 10.1124/mol.117.108654
A1 Maroua Jalouli
A1 Sophie Mokas
A1 Catherine A Turgeon
A1 Laurent Lamalice
A1 Darren E Richard
YR 2017
UL http://molpharm.aspetjournals.org/content/early/2017/08/16/mol.117.108654.abstract
AB Hypoxia-inducible factor-1 (HIF-1) is a key gene regulator for cellular adaptation to low oxygen. In addition to hypoxia, several nonhypoxic stimuli, including hormones and growth factors, are an essential part for cell-specific HIF-1 regulation. Our studies have highlighted angiotensin II (AngII), a vasoactive hormone, as a potent HIF-1 activator in vascular smooth muscle cells (VSMC). AngII increases HIF-1 transcriptional activity by modulating specific signaling pathways. In VSMC, p42/p44 mitogen-activated protein kinase (MAPK) pathway activation is essential for HIF-1-mediated transcription during AngII treatment. The present study shows that PD184161, a potent MEK1/2 inhibitor, is a HIF-1 blocker in Ang II-treated VSMC. Unlike PD98059, a widely-used MEK1/2 inhibitor, we found that PD184161 blocked AngII-driven HIF-1α protein induction in a dose-dependent manner. Interestingly, the effect of PD184161 was specific to nonhypoxic activators, since HIF-1α induction by hypoxia (1% O2) was unaffected under similar conditions. VSMC treatment with MG132, a proteasome inhibitor, indicated that PD184161 influenced HIF-1α protein stability. PD184161 also increased HIF-1α binding to VHL, a E3 ligase component and an indication of HIF-1α hydroxylation. Finally, we show that PD184161 blocked mitochondrial ROS (mtROS) production and cellular ATP levels, while enhancing ascorbate availability in AngII-treated VSMC. Taken together, our study indicates that, independently of p42/p44MAPK activation, PD184161 blocks mtROS generation by AngII, leading to reestablishment of cellular ascorbate levels, increased VHL binding and decreased HIF-1α stability. Therefore, this study reveals a previously unsuspected role for PD184161 as a HIF-1 inhibitor in VSMC under nonhypoxic conditions.