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KLF2 Upregulates miR-483 to Modulate Endothelial Function

  • Author(s): Woo, Brian Justin
  • Advisor(s): Shyy, John
  • et al.
Abstract

.KLF2, originally named lung kruppel-like factor (LKLF), is a zinc finger transcription factor that is heavily involved in vascular development. Recent studies have identified this shear stress responsive gene as a key regulator of endothelial function by modulating endothelial quiescence and vascular tone. Key molecules involved in vascular function such as endothelial nitric oxide synthetase (eNOS) and thrombomodulin have been demonstrated to be direct downstream targets of KLF2. Furthermore, KLF2 upregulation is also associated with downregulation of adhesion molecules and inflammatory cytokines providing an atheroprotective effect. Like other members of the KLF family, KLF2 binds the DNA motif `CACCC' to regulate expression of downstream targets. In vivo, KLF2 is upregulated by pulsatile shear stress conferring an atheroprotective effect. The HMG-CoA reductase inhibitor, statins, have also been shown to upregulate KLF2 via an AMPK dependent mechanism.

We hypothesize that the KLF2 can directly regulate miRNA expression through binding of regulatory regions to promote or repress transcription. The change in miRNA expression can be one means by which KLF2 promotes an atheroprotective effect. Towards this end, we performed a genome wide search for putative KLF2 binding sequences within the regulatory regions of shear stress responsive miRNAs. Preliminary experiments, have demonstrated that miR-483 is upregulated by pulsatile shear stress, statin treatment, as well as KLF2 overexpression. We hypothesize that the upregulation of miR-483 can result in transcriptional repression of a subset of KLF2 responsive genes. Angiotensin Converting Enzyme (ACE) is key enzyme in the rennin-angiotensin system responsible for regulation of blood pressure via the cleavage of the Angiotensin I to the active peptide, Angiotensin II. Akt2 is a serine/threonine kinase that is involved in cell functions including proliferation, growth, and inflammation. Bioinformatics predictions as well as preliminary data have demonstrated that these genes could be a potential target of miR-483.

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