OBJECTIVE: Atheroprotective blood flow induces expression of anti-inflammatory Krüppel-like factor 2 (KLF2) and activates antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in vascular endothelium. Previously, we obtained KLF2-induced gene expression profiles in ECs, containing several Nrf2 target genes. Our aim was to investigate the role of KLF2 in shear stress-mediated activation of Nrf2 in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: Expression of Nrf2 and its targets NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase (HO-1) was elevated by shear and KLF2. KLF2 knockdown showed that shear-induced expression of NQO1 but not Nrf2 was dependent on KLF2. KLF2 overexpression in absence of flow resulted in more efficient activation of Nrf2 by tert-butyl hydroquinone (tBHQ) through enhanced nuclear localization, and promoted expression of a large panel of Nrf2-dependent genes resulting in superior protection against oxidative stress. Comparison of shear-, KLF2-, and Nrf2-induced transcriptomes showed that the majority of shear-modulated gene sets is influenced by KLF2 or Nrf2. CONCLUSIONS: We report that KLF2 substantially enhances antioxidant activity of Nrf2 by increasing its nuclear localization and activation. The synergistic activity of these two transcription factors forms a major contribution to the shear stress-elicited transcriptome in endothelial cells.
OBJECTIVE: Atheroprotective blood flow induces expression of anti-inflammatory Krüppel-like factor 2 (KLF2) and activates antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in vascular endothelium. Previously, we obtained KLF2-induced gene expression profiles in ECs, containing several Nrf2 target genes. Our aim was to investigate the role of KLF2 in shear stress-mediated activation of Nrf2 in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: Expression of Nrf2 and its targets NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase (HO-1) was elevated by shear and KLF2. KLF2 knockdown showed that shear-induced expression of NQO1 but not Nrf2 was dependent on KLF2. KLF2 overexpression in absence of flow resulted in more efficient activation of Nrf2 by tert-butyl hydroquinone (tBHQ) through enhanced nuclear localization, and promoted expression of a large panel of Nrf2-dependent genes resulting in superior protection against oxidative stress. Comparison of shear-, KLF2-, and Nrf2-induced transcriptomes showed that the majority of shear-modulated gene sets is influenced by KLF2 or Nrf2. CONCLUSIONS: We report that KLF2 substantially enhances antioxidant activity of Nrf2 by increasing its nuclear localization and activation. The synergistic activity of these two transcription factors forms a major contribution to the shear stress-elicited transcriptome in endothelial cells.
Authors: Qing Qing Wu; Yanxia Wang; Martin Senitko; Colin Meyer; W Christian Wigley; Deborah A Ferguson; Eric Grossman; Jianlin Chen; Xin J Zhou; John Hartono; Pamela Winterberg; Bo Chen; Anapam Agarwal; Christopher Y Lu Journal: Am J Physiol Renal Physiol Date: 2011-02-02
Authors: Evgeny A Zemskov; Qing Lu; Wojciech Ornatowski; Christina N Klinger; Ankit A Desai; Emin Maltepe; Jason X-J Yuan; Ting Wang; Jeffrey R Fineman; Stephen M Black Journal: Antioxid Redox Signal Date: 2019-03-19 Impact factor: 8.401
Authors: Biji Mathew; Jeffrey R Jacobson; Jessica H Siegler; Jaideep Moitra; Michael Blasco; Lishi Xie; Crystal Unzueta; Tong Zhou; Carrie Evenoski; Mohammed Al-Sakka; Rajesh Sharma; Ben Huey; Aydogan Bulent; Brett Smith; Sundararajan Jayaraman; Narsa M Reddy; Shekhar P Reddy; Günter Fingerle-Rowson; Richard Bucala; Steven M Dudek; Viswanathan Natarajan; Ralph R Weichselbaum; Joe G N Garcia Journal: Am J Respir Cell Mol Biol Date: 2013-08 Impact factor: 6.914