regulation of enos expression by nfkb, shear stress, and exercise
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Publication
Journal: Journal of Clinical Investigation
October/5/2014
Abstract
In atherosclerosis, plaques preferentially develop in arterial regions of disturbed blood flow (d-flow), which alters endothelial gene expression and function. Here, we determined that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase-dependent (DNMT-dependent) manner. Induction of d-flow by partial carotid ligation surgery in a murine model induced DNMT1 in arterial endothelium. In cultured endothelial cells, DNMT1 was enhanced by oscillatory shear stress (OS), and reduction of DNMT with either the inhibitor 5-aza-2'-deoxycytidine (5Aza) or siRNA markedly reduced OS-induced endothelial inflammation. Moreover, administration of 5Aza reduced lesion formation in 2 mouse models of atherosclerosis. Using both reduced representation bisulfite sequencing (RRBS) and microarray, we determined that d-flow in the carotid artery resulted in hypermethylation within the promoters of 11 mechanosensitive genes and that 5Aza treatment restored normal methylation patterns. Of the identified genes, HoxA5 and Klf3 encode transcription factors that contain cAMP response elements, suggesting that the methylation status of these loci could serve as a mechanosensitive master switch in gene expression. Together, our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.
Publication
Journal: Antioxidants and Redox Signaling
November/30/2009
Abstract
NADPH oxidases (Nox) have been the subject of very intensive research over the past several years, which has led to in-depth understanding of the function of these enzymes in health and disease. Discovery of novel Nox enzymes and identification of a very wide range of tissue expression has increased our understanding of how NADPH oxidases may regulate so many distinct cellular functions and how the dysfunction of these enzymes may lead to disease. The present Forum issue summarizes the most novel aspects of NADPH oxidase biology, focusing on linking the molecular basis of NADPH oxidase function, compartmentalization, and differential expression patterns to diseases such as those of the pulmonary system, inflammation, central nervous system disorders, endothelial and vascular dysfunction, as well as disorders involving angiogenesis and stem cell and endothelial progenitor cell functions. Establishing these links may be the first step for future therapeutic use of NADPH oxidase inhibitors, which are discussed at length within this Forum issue.