Journal Article

Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice

Feaver, Ryan E., Jain, Mukesh K., Nayak, Lalitha, Sharma, Nikunj, Boerboom, Lauren, Desai, Amar, Gerson, Stanton L., Simon, Daniel I., Atkins, G. Brandon, Wang, Yunmei, Hale, Andrew, Liao, Xudong, Lu, Yuan, Zhou, Guangjin, Schmaier, Alvin, Hamik, Anne, Tian, Hongmei, Gao, Huiyun, Shi, Hong, Blackman, Brett R.

2012

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animal models / Animals / Atheroembolism / Atherogenesis / Atherosclerosis / Atherosclerosis - metabolism / Biomechanics / Biomedical research / Blood clot / Brief Report / Cells, Cultured / Competition / Cytokines / Endothelium / Gene expression / Gene Expression Regulation / Gene flow / Genetic aspects / Homeostasis / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Inflammation / KLF4 protein / Kruppel-Like Transcription Factors - genetics / Kruppel-Like Transcription Factors - metabolism / Kruppel-Like Transcription Factors - physiology / Mice / Mice, Inbred C57BL / Mice, Transgenic / p300-CBP Transcription Factors - metabolism / Prevention / Protein Binding / Protein Interaction Domains and Motifs / Risk factors / Shear stress / Thrombosis / Thrombosis - genetics / Thrombosis - metabolism / Transplants & implants / Vasculitis - metabolism