Fluid shear stress induces endothelial KLF2 gene expression through a defined promoter region

Abstract

Fluid shear stress is crucial for maintenance of a properly functioning endothelium. In this study we demonstrate that the KLF2 transcription factor is greatly induced by pulsatile shear stress in murine microvascular endothelial cells. The promoter elements responsible for the induction were studied by transfection with luciferase-reporter plasmids including the 5' flanking region of the murine KLF2 gene. Deletion analysis reveals that the responses are regulated by a region from -157 to -95 bp from the start site of transcription. Furthermore, shear stress induces specific nuclear binding within this region. These results define a novel shear stress response region that is highly conserved between mouse and human homologs.

Bacterial Toxins Induce Sustained mRNA Expression of the Silencing Transcription Factor klf2 via Inactivation of RhoA and Rhophilin 1

“…Tumor necrosis factor receptor-associated factor 2 (TRAF2) and signaling via p38 mitogen-activated protein kinase (MAPK), but not tumor necrosis factor signaling, have been suggested to regulate klf2 mRNA expression (34). In both human and mouse cells, critical regions within the klf2 promoter have been identified (27,57), and heterogeneous nuclear ribonucleoproteins as well as acetyltransferases have been shown to bind to these regions (3). Other results suggest that statin-mediated klf2 induction in endothelial cells is a result of interference with Rho signaling (58), although the precise mechanism remains obscure.…”

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

“…(B) HUVECs were cultured under static (no flow), atheroprone, or atheroprotective flow conditions for 24 hours, and KLF2 mRNA expression was measured by RT-PCR (n = 3; mean ± SEM). nar shear stress (12). To gain insights into possible mechanisms leading to upregulation of KLF2 by flow, we analyzed the proximal promoter for transcription factor consensus binding sequences and found them to include a myocyte enhancer factor-2 (MEF2) site.…”

The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis

“…Currently, one of the best characterised of these genes encodes the zinc finger transcription factor Krüppel-like factor 2 (Klf2) (Novodvorsky and Chico, 2014). The human and murine KLF2/Klf2 genes possess a shear stressresponsive promotor element that is evolutionarily conserved (Huddleson et al, 2004(Huddleson et al, , 2005 and are expressed in regions of high shear stress (Dekker et al, 2002;Groenendijk et al, 2004Groenendijk et al, , 2005. Within the zebrafish atrioventricular canal, high oscillatory flow increases klf2a expression, which, as indicated by morpholinomediated knockdown studies, is required for zebrafish valve development (Heckel et al, 2015;Vermot et al, 2009).…”