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(Circulation. 2005;112:720-726.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Kruppel-Like Factor 2 as a Novel Mediator of Statin Effects in Endothelial Cells

Sucharita Sen-Banerjee, PhD^*; Samy Mir, MD^*; Zhiyong Lin, PhD; Anne Hamik, MD, PhD; G. Brandon Atkins, MD, PhD; Hiranmoy Das, PhD; Pallab Banerjee, PhD; Ajay Kumar, PhD; Mukesh K. Jain, MD

From the Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Dr Banerjee is currently at the Department of Radiology, University of Massachusetts Medical School, Worcester, Mass.

Correspondence to Mukesh K. Jain, MD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail mjain{at}rics.bwh.harvard.edu

Received November 29, 2004; revision received April 11, 2005; accepted April 19, 2005.

Background— Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to modulate endothelial function, the transcriptional mechanisms underlying these effects are incompletely understood. We hypothesized that Lung-Kruppel–like factor (LKLF/KLF2), a novel and potent regulator of endothelial gene expression, may mediate the downstream effects of statins. Here we report that statin-induced expression of endothelial NO synthase (eNOS) and thrombomodulin is KLF2 dependent.

Methods and Results— KLF2 mRNA was induced by treatment with multiple statins in a concentration-dependent manner. Multiple lines of evidence suggest that this induction is dependent on inhibition of the Rho pathway and requires de novo transcription. Furthermore, promoter deletion and mutational analyses suggest that mevastatin induced KLF2 promoter activity through a single myocyte enhancer factor binding site. Finally, small-interfering RNA–mediated knockdown of KLF2 strongly attenuated the ability of mevastatin to increase eNOS and thrombomodulin accumulation in endothelial cells.

Conclusions— Taken together, these observations indicate that statin-dependent induction of eNOS and thrombomodulin requires KLF2 and thereby provides a novel molecular target for modulating endothelial function in vascular disease.

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