Regulation of KLF2 by Haemodynamic Forces

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KLF2 was first shown to be one of a small number of genes upregulated in cultured human endothelial cells exposed to laminar shear stress for 7 days when compared to static (no flow) culture conditions (Dekker et al. 2002). Using in situ hybridisation of adult human arteries, these authors demonstrated that KLF2 expression was restricted to the endothelium within the vessel wall, and that the pattern of expression correlated with predicted types of shear stress. Specifically, endothelial expression of KLF2 was highest in regions that are predicted to be exposed to laminar shear stress, and thus resistant to atherosclerosis, and comparatively absent in atheroprone regions exposed to non-laminar shear stress (e.g. bifurcations). Based on these observations, Dekker et al. hypothesised a potential role for KLF2 in atherogenesis (Dekker et al. 2002). The response of KLF2 expression to laminar shear stress in vitro has since been confirmed by other groups including our own (Huddleson et al. 2004; SenBanerjee et al. 2004).

Furthermore, complex modelling of the arterial waveforms characteristic of the in vivo atherosclerosis-resistant (atheroprotective flow) and atherosclerosis-prone (atheroprone flow) regions of the human carotid artery also demonstrates a selective upregulation of KLF2 by atheroprotective flow as determined by transcriptional profiling (Fig. 4; Dai et al. 2004). Dissection of the basic biomechanical parameters relevant to KLF2 induction revealed an increased effect of pulsatile flow compared to non-pulsatile laminar flow, and no KLF2 response to cyclic stretch (Dekker et al. 2005). In vivo studies in silent heart mutant zebrafish, which lack blood flow yet remain viable and functional for several days, demonstrate the absence of vascular endothelial KLF2a (the

Fig. 4 Expression of the transcription factor KLF2 is differentially responsive to distinct haemodynamic environments and is regulated by statins. Human umbilical vein endothelial cells (HUVECs) were cultured under static (no flow), "atheroprone" or "atheroprotective" flow conditions for 24 h (leftpanel). HUVECs were also cultured for 24 h in normal medium, medium with ethanol vehicle, or 100-nM and 1-|M concentrations of simvastatin, lovastatin and cerivastatin (rightpanel). Kruppel-like factor-2 (KLF2) mRNA expression was measured by real-time Taqman PCR. All data are expressed as mean+/-SE

Fig. 4 Expression of the transcription factor KLF2 is differentially responsive to distinct haemodynamic environments and is regulated by statins. Human umbilical vein endothelial cells (HUVECs) were cultured under static (no flow), "atheroprone" or "atheroprotective" flow conditions for 24 h (leftpanel). HUVECs were also cultured for 24 h in normal medium, medium with ethanol vehicle, or 100-nM and 1-|M concentrations of simvastatin, lovastatin and cerivastatin (rightpanel). Kruppel-like factor-2 (KLF2) mRNA expression was measured by real-time Taqman PCR. All data are expressed as mean+/-SE

homologue of the mammalian KLF2) expression in the aorta and cardinal vein (Parmar et al. 2005a). These observations demonstrate that endothelial KLF2 expression is dependent on blood flow in vivo and that this mode of regulation may be evolutionarily conserved.

Further in vitro analyses performed in our laboratories have revealed that the mechanisms linking haemodynamic forces and KLF2 expression involve activation of a MEK5/ERK5/MEF pathway and that MEK5 activation is indeed necessary and sufficient for the flow-mediated upregulation of KLF2 in vascular endothelium. These results are consistent with a model in which flow activates MEK5, which in turn phosphorylates ERK5, resulting in the activation of the MEF2 family of transcription factors at the KLF2 promoter. Interestingly, we demonstrated that binding of the MEF2 members to the KLF2 promoter is found under static conditions and is not substantially altered upon the exposure of endothelial cells to flow, indicating that this transcription factor appears to bind tonically to the KLF2 promoter and act as a "switch" by receiving upstream signals (Parmar et al. 2005a).

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