Regulation of Vascular Inflammation and Remodeling by ETS Factors Peter Oettgen

Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Circulation Research (Impact Factor: 11.02). 12/2006; 99(11):1159-66. DOI: 10.1161/01.RES.0000251056.85990.db
Source: PubMed


The ETS (E26 Transformation-specific Sequence) factors are comprised of a family of transcription factors that share a highly conserved DNA binding domain. Although originally described for their role as protooncogenes in the development of several types of human cancer, they have subsequently been shown to regulate a wide variety of biological processes including cellular growth and differentiation under normal and pathological conditions. As transcription factors, they can either function as activators or repressors of gene expression. Several ETS family members are expressed in cells of vascular origin, including endothelial cells and vascular smooth muscle cells, where they regulate the expression of a number of vascular-specific genes. In the past few years, emerging evidence supports a novel role for selected ETS family members in the regulation of vascular inflammation and remodeling. ETS factor expression can be induced by proinflammatory cytokines, growth factors, and vasoactive peptides. Examples of some of the target genes regulated by ETS factors include adhesion molecules, chemokines, and matrix metalloproteinases. Targeted disruption of selected ETS family members such as Ets-1 in mice is associated with marked reductions in the recruitment of inflammatory cells and vascular remodeling in response to systemic administration of the vasoactive peptide angiotensin II. The purpose of this review is to provide an overview of recent advances that have been made in defining a role for selected members of the ETS transcription factor family in the regulation of vascular-specific gene expression, vascular inflammation, and remodeling.

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    • "Furthermore, injured ECs express proinflammatory soluble and membrane bound mediators, including chemokines and p-selectin and vascular cell adhesion molecule-1 (VCAM-1), which increase leukocyte trafficking, as well as von Willebrand factor (VWF) which promotes thrombosis [13]. Several inflammatory pathways in the vasculature have been well defined [14]. For example, oxidized LDL can activate the nuclear factor κB (NF-κB) pathway, inducing the expression of a set of inflammatory genes [15]. "
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    ABSTRACT: Vascular inflammation is an important component of the pathophysiology of cardiovascular diseases, such as hypertension, atherosclerosis, and aneurysms. All vascular cells, including endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and infiltrating cells, such as macrophages, orchestrate a series of pathological events. Despite dramatic improvements in the treatment of atherosclerosis, the molecular basis of vascular inflammation is not well understood. In the last decade, microRNAs (miRNAs) have been revealed as novel regulators of vascular inflammation. Each miRNAs suppresses a set of genes, forming complex regulatory network. This paper provides an overview of current advances that have been made in revealing the roles of miRNAs during vascular inflammation. Recent studies show that miRNAs not only exist inside cells but also circulate in blood. These circulating miRNAs are useful biomarkers for diagnosis of cardiovascular diseases. Furthermore, recent studies demonstrate that circulating miRNAs are delivered into certain recipient cells and act as messengers. These studies suggest that miRNAs provide new therapeutic opportunities.
    International journal of vascular medicine 09/2012; 2012:794898. DOI:10.1155/2012/794898
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    • "Serial deletions of the 3'-end of the ALG12 promoter lacking the middle intergenic region revealed that there is a suppressive site from position -75 to -16 in the ALG12 promoter (Figure 6B). Deletion around three putative Ets family binding sites (TTCC) [21,22] from position -52 to -20 (Figure 2, site III) in the ALG12 promoter (-343/-212 & -107/+11 m1) also restored responsiveness to Tg. Yet, this same site III deletion in the ALG12 promoter containing the middle intergenic region (-361/+11 m3) showed unresponsiveness to Tg (Figure 6C). "
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    ABSTRACT: Recently, we identified cysteine-rich with EGF-like domains 2 (CRELD2) as a novel endoplasmic reticulum (ER) stress-inducible gene and characterized its transcriptional regulation by ATF6 under ER stress conditions. Interestingly, the CRELD2 and asparagine-linked glycosylation 12 homolog (ALG12) genes are arranged as a bidirectional (head-to-head) gene pair and are separated by less than 400 bp. In this study, we characterized the transcriptional regulation of the mouse CRELD2 and ALG12 genes that is mediated by a common bidirectional promoter. This short intergenic region contains an ER stress response element (ERSE) sequence and is well conserved among the human, rat and mouse genomes. Microarray analysis revealed that CRELD2 and ALG12 mRNAs were induced in Neuro2a cells by treatment with thapsigargin (Tg), an ER stress inducer, in a time-dependent manner. Other ER stress inducers, tunicamycin and brefeldin A, also increased the expression of these two mRNAs in Neuro2a cells. We then tested for the possible involvement of the ERSE motif and other regulatory sites of the intergenic region in the transcriptional regulation of the mouse CRELD2 and ALG12 genes by using variants of the bidirectional reporter construct. With regards to the promoter activities of the CRELD2-ALG12 gene pair, the entire intergenic region hardly responded to Tg, whereas the CRELD2 promoter constructs of the proximal region containing the ERSE motif showed a marked responsiveness to Tg. The same ERSE motif of ALG12 gene in the opposite direction was less responsive to Tg. The direction and the distance of this motif from each transcriptional start site, however, has no impact on the responsiveness of either gene to Tg treatment. Additionally, we found three putative sequences in the intergenic region that antagonize the ERSE-mediated transcriptional activation. These results show that the mouse CRELD2 and ALG12 genes are arranged as a unique bidirectional gene pair and that they may be regulated by the combined interactions between ATF6 and multiple other transcriptional factors. Our studies provide new insights into the complex transcriptional regulation of bidirectional gene pairs under pathophysiological conditions.
    BMC Genomics 11/2010; 11(1):664. DOI:10.1186/1471-2164-11-664 · 3.99 Impact Factor
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