Sirt1 decreases TLR2-mediated Mac-1 expression in atherosclerosis

Abstract

Abstract Sirtuin (Sirt) 1 has been demonstrated to exerts protective effects in the progression of atherosclerosis, however, the underlying mechanisms are unclear. Thus, this study investigated the the role of Sirt1 in TLR2-mediated monocyte adhesion to vascular endothelium, which is a key early event in macrophage foam cell formation. The atherosclerotic lesion formation in aortic sinus was significantly increased in Pam3CSK4-treated wild type (WT) mice, which was significantly inhibited in Sirt1 Tg mice group. An en face immunohistochemistry of endothelial surfaces revealed a marked increase in monocyte adhesion to aortic endothelium in WT mice treated with Pam3CSK4, which was significantly attenuated in Sirt1 Tg mice. Likewise, the adhesion capacity of primary monocytes isolated from Pam3CSK4-treated WT mice was higher than those of monocytes from Sirt1 Tg mice. In in vitro study, Pam3CSK4 increased monocyte adhesion to endothelial cells with an enhanced Mac-1 expression. These were attenuated by a recombinant Sirt1, as well as by molecular overexpression of Sirt1 in monocytes. In addition, we found that Pam3CSK4-reduced Sirt1 expression in monocytes was regulated by the transcription factors, NF-kB and CREB. The role of NF-kB and CREB in Pam3CSK4-reduced Sirt expression was confirmed by siRNA knockdown of Sp1 and NF-kB. Sirt1 supresses atherosclerosis progression by TLR2-mediated monocyte adhesion to endothelium through Mac-1 expression, which is mediated by NF-kB and CREB pathways in monocytes, consequently leading to the development of therapeutic interventions for regulating Sirt1 expression in atherosclerosis.