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Download or read book Mechanisms of the Anti-inflammation Action of Pulsatile Laminar Flow written by Leona Marie Flores and published by . This book was released on 2010 with total page 91 pages. Available in PDF, EPUB and Kindle. Book excerpt: Pulsatile laminar flow (PS) mediates various anti-inflammatory and anti-proliferative functions in endothelial cells (ECs) through the upregulation of atheroprotective molecules such as Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). However, the mechanisms involved in the repression of inflammatory responses by mechanical stimuli have not been elucidated. In human umbilical vein endothelial cells (HUVECs), 24-hr PS (12 " 4 dynes/cm2) inhibited the gene expression of inflammatory and adhesion molecules monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM) and E-selectin (SELE). Using Compound C, an AMP-activated protein kinase (AMPK) specific inhibitor, I found that the inhibition of gene expression by PS was dependent on the activity of AMPK. In assessing the functional consequences of the PS-inhibition of adhesion molecule expression, I found that PS attenuated monocyte attachment to ECs and that this effect was reversed under Compound C treatment, suggesting the requirement of AMPK in the reduction of monocyte attachment by PS. Recent studies suggest a key role for epigenetics in the pathogenesis of human disease, especially those involving inflammatory responses, and have established epigenetic pathways as fundamental determinants of endothelial gene expression. In concert with the finding on PS-induced gene repression, I have shown that PS induced the recruitment of the corepressor enzyme histone deacetylase-5 (HDAC5) to the MCP-1 and VCAM proximal promoters and that this recruitment was associated with a histone hypoacetylation status on these promoters. Furthermore, these PS-regulated epigenetic changes were demonstrated to be AMPK-dependent. In examining the relationship among shear stress, epigenetic dynamics, and inflammatory responses, I have demonstrated that PS exerts anti-inflammatory effects on ECs through downregulation of inflammatory gene expression and functional responses, and via recruitment of corepressors with subsequent histone modifications. Furthermore, I have established that these responses are dependent on the AMPK signaling pathway. This study has contributed to the understanding of the anti-inflammatory mechanisms in vascular cells, especially on the roles of intracellular mediators and epigenetic elements in the PS-induced downregulation of inflammatory processes, which are implicated in the early development of atherosclerosis.