This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/4/369    most recent CIRCRESAHA.108.174607v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fu, Q. Articles by Hauer-Jensen, M. Search for Related Content PubMed PubMed Citation Articles by Fu, Q. Articles by Hauer-Jensen, M.

(Circulation Research. 2008;103:369.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Involvement of Heat Shock Factor 1 in Statin-Induced Transcriptional Upregulation of Endothelial Thrombomodulin

Qiang Fu, Junru Wang, Marjan Boerma, Maaike Berbée, Xiaohua Qiu, Louis M. Fink, Martin Hauer-Jensen

From the Departments of Microbiology and Immunology (Q.F.), Surgery (J.W., M.B., X.Q., M.H.-J.), Pharmaceutical Sciences (M.B.), and Pathology (M.H.-J.), University of Arkansas for Medical Sciences, Little Rock, Ark; Nevada Cancer Institute (L.M.F.), Las Vegas, Nev; and the Surgery Service (M.H.-J.), Central Arkansas Veterans Healthcare System, Little Rock, Ark.

Correspondence to Martin Hauer-Jensen, MD, PhD, Winthrop P. Rockefeller Cancer Institute, 4301 West Markham, Slot 725, Little Rock, AR 72205. E-mail mhjensen{at}life.uams.edu

Statins upregulate endothelial thrombomodulin (TM) by mechanisms that involve members of the Kruppel-like factor family. Although Kruppel-like factors are unequivocally implicated in this process, experimental evidence points to additional mechanisms. Deletion/mutation analysis of reporter constructs was used to demonstrate that mutation of the SP1/Kruppel-like factor element in the TM promoter only partially abolishes statin-induced TM upregulation, whereas simultaneous mutation of relevant heat shock elements and SP1/Kruppel-like factor element completely prevents statin-induced TM upregulation, thus demonstrating a role for heat shock factors (HSFs). We further identified the pathway by which statins increase binding of HSF1 to heat shock elements in the TM promoter. Specifically, statins caused NO-dependent dissociation of HSF1 from heat shock protein 90, nuclear translocation of HSF1, and binding to heat shock elements in the TM promoter. Statins also decreased nuclear content of the HSF1 chaperone 14-3-3β. In addition to reducing TM upregulation, inhibition of HSF1 reduced statin-induced upregulation of tissue plasminogen activator, whereas downregulation of thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor was unaffected. Knockdown of 14-3-3β or inhibition of HSF1 phosphorylation enhanced the effect of statins on TM and tissue plasminogen activator, but did not influence thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor. These data demonstrate that HSF1 is involved in statin-induced regulation of TM. They also suggest that analogous mechanisms may apply to genes that are upregulated by statins, but not to downregulated genes. These results may have broad implications and suggest the use of heat shock protein modulators to selectively regulate pleiotropic statin effects.

Key Words: endothelial cells • heat shock proteins • thrombomodulin • transcriptional regulation

This article has been cited by other articles:

				E. Kansanen, H.-K. Jyrkkanen, O. L. Volger, H. Leinonen, A. M. Kivela, S.-K. Hakkinen, S. R. Woodcock, F. J. Schopfer, A. J. Horrevoets, S. Yla-Herttuala, et al. Nrf2-dependent and -independent Responses to Nitro-fatty Acids in Human Endothelial Cells: IDENTIFICATION OF HEAT SHOCK RESPONSE AS THE MAJOR PATHWAY ACTIVATED BY NITRO-OLEIC ACID J. Biol. Chem., November 27, 2009; 284(48): 33233 - 33241. [Abstract] [Full Text] [PDF]

				F. Arslan, G. Pasterkamp, and D. P. de Kleijn Unraveling Pleiotropic Effects Of Statins: Bit By Bit, a Slow Case With Perspective Circ. Res., August 15, 2008; 103(4): 334 - 336. [Full Text] [PDF]