Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice.

Pubmed ID: 23160196

Pubmed Central ID: PMC3533563

Journal: The Journal of clinical investigation

Publication Date: Dec. 1, 2012

Affiliation: Case Cardiovascular Research Institute, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.

MeSH Terms: Humans, Cells, Cultured, Animals, Atherosclerosis, Mice, Gene Expression Regulation, Vasculitis, Human Umbilical Vein Endothelial Cells, Thrombosis, Protein Binding, Kruppel-Like Transcription Factors, Mice, Inbred C57BL, Mice, Transgenic, Protein Interaction Domains and Motifs, p300-CBP Transcription Factors, Kruppel-Like Factor 4

Grants: HL052779, R21 HL112666, HL076754, HL082836, HL083090, HL086548, HL088740, HL097593, HL102951, HL110630, HL112486L, HL112666A, HL57506, HL85816, R01 HL097593, R01 HL110630, R01 HL119195, R37 HL057506, R01 HL052779, R01 HL085816, R01 HL076754, R01 HL112486, R01 HL057506, R01 HL086548, R01 HL082836, K08 HL083090, R44 HL102951, K01 HL088740, R43 HL102951

Authors: Wang Y, Lu Y, Zhou G, Hamik A, Nayak L, Tian H, Shi H, Sharma N, Liao X, Hale A, Boerboom L, Feaver RE, Gao H, Desai A, Schmaier A, Gerson SL, Atkins GB, Blackman BR, Simon DI, Jain MK

Cite As: Zhou G, Hamik A, Nayak L, Tian H, Shi H, Lu Y, Sharma N, Liao X, Hale A, Boerboom L, Feaver RE, Gao H, Desai A, Schmaier A, Gerson SL, Wang Y, Atkins GB, Blackman BR, Simon DI, Jain MK. Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice. J Clin Invest 2012 Dec;122(12):4727-31. Epub 2012 Nov 19.

Studies:

Abstract

The endothelium regulates vascular homeostasis, and endothelial dysfunction is a proximate event in the pathogenesis of atherothrombosis. Stimulation of the endothelium with proinflammatory cytokines or exposure to hemodynamic-induced disturbed flow leads to a proadhesive and prothrombotic phenotype that promotes atherothrombosis. In contrast, exposure to arterial laminar flow induces a gene program that confers a largely antiadhesive, antithrombotic effect. The molecular basis for this differential effect on endothelial function remains poorly understood. While recent insights implicate Kruppel-like factors (KLFs) as important regulators of vascular homeostasis, the in vivo role of these factors in endothelial biology remains unproven. Here, we show that endothelial KLF4 is an essential determinant of atherogenesis and thrombosis. Using in vivo EC-specific KLF4 overexpression and knockdown murine models, we found that KLF4 induced an antiadhesive, antithrombotic state. Mechanistically, we demonstrated that KLF4 differentially regulated pertinent endothelial targets via competition for the coactivator p300. These observations provide cogent evidence implicating endothelial KLFs as essential in vivo regulators of vascular function in the adult animal.