![]() ![]() High-shear stress at the endothelial surface induces KLF2, reducing inflammatory activation and antithrombotic properties 18, 19, 20. Of the many factors identified, the zinc finger transcription factor Krüppel-like factor (KLF2) 13 has emerged as a master regulator of the atheroprotective transcriptional program in the endothelium 14, 15 and in various myeloid-derived cell types 16, 17. The consistent message coming out from such studies is that a healthy blood flow provokes an endothelial transcriptional program characterized by increased expression of anti-inflammatory, anti-adhesive and anti-thrombotic factors 6, 12. These studies have been extensively recapitulated in in vitro studies on endothelial cell monolayers under shear stress conditions 11. ![]() Gene expression studies have demonstrated major differences in the transcriptional profile exerted upon the endothelium by a healthy, laminar blood flow compared to the complex and turbulent flow associated with early sites of atherosclerotic lesions 6, 9, 10. It is now evident that biomechanical forces exerted upon the endothelial layers by blood flow play a significant role in the resolution of inflammatory insults 7, 8. The classical view states that the initial step of inflammation during atherosclerosis depends on the activation of the vascular endothelium 6. A compelling body of evidence now describes the importance of endothelial dysfunction and inflammation during the development of atherosclerosis 2, evidence which has driven the pharmaceutical industry to target inflammatory pathways in the quest for novel therapeutic strategies 3, 4, 5. Without access to new, inexpensive treatments, atherosclerosis and its associated cardiovascular complications will likely remain a leading cause of morbidity and mortality worldwide 1. Similar content being viewed by othersĪtherosclerosis poses a significant burden to healthcare systems throughout the world. Our data suggest that inclusion of bioactive solvent NMP in pharmaceutical compositions to treat inflammatory disorders might be beneficial and safe, in particular to treat diseases of the vascular system, such as atherosclerosis. Our findings demonstrate a consistent effect of NMP upon KLF2 activation and inflammation, biological processes central to atherogenesis. Enhancing KLF2 expression and activity improves endothelial function, controls multiple genes critical for inflammation, and prevents atherosclerosis. We further show using KLF2 shRNA that the inhibitory effect of NMP on endothelial inflammation and subsequent monocyte adhesion is KLF2 dependent. We found that NMP attenuates monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha (TNF-α) by reducing expression of adhesion molecules. ![]() Monocytes and endothelial cells treated with NMP express increased levels of KLF2, produce less pro-inflammatory cytokines and adhesion molecules. Mechanistically, NMP increases the expression of the transcription factor Kruppel-like factor 2 (KLF2). Here, we report that NMP is a bioactive anti-inflammatory compound well tolerated in vivo, that shows efficacy in reducing disease in a mouse model of atherosclerosis. It is used as a drug solubilizer and penetration enhancer in human and animal, yet its bioactivity properties remain elusive. ![]() N-methyl-2-pyrrolidone (NMP) is a versatile water-miscible polar aprotic solvent. ![]()
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