High-level expression of Egr-1 and Egr-1–inducible genes in mouse and human atherosclerosis

McCaffrey, Timothy A.; Fu, Chenzhong; Du, Baoheng; Eksinar, Sukru; Kent, K. Craig; Bush, Harry L.; Kreiger, Karl H.; Rosengart, Todd K.; Cybulsky, Myron I.; Silverman, Eric S.; Collins, Tucker

doi:10.1172/jci8592

Cited by 273 publications

(222 citation statements)

References 58 publications

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“…Similar to observations in our study, EGR1, an early response transcriptional factor previously associated with atherosclerosis (McCaffrey et al 2000), was one of the most up-regulated of the 267 genes identified in their screen. In retrospective analysis, EGR1 was also expressed at higher levels in our patient versus control monocytes though it was not significantly increased in our SAGE libraries (Patino et al 2005).…”

Section: Concordance Of Transcriptional Studies Of Human Atherosclerosupporting

confidence: 90%

Genomic Analysis of Circulating Cells: A Window Into Atherosclerosis

Kang

Patino

Matoba

et al. 2006

Trends in Cardiovascular Medicine

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Translational studies using genomic techniques in cardiovascular diseases are still in their infancy. Access to disease-associated cardiovascular tissues from patients has been a major impediment to progress in contrast to the diagnostic advances made by oncologists using gene expression on readily available tumor samples. Nonetheless, progress is being made for atherosclerosis by carefully designed experiments using diseased tissue or surrogate specimens. This review details the rationale and findings of a study using freshly isolated blood mononuclear cells from patients undergoing carotid endarterectomy due to atherosclerotic stenosis and from matched normal subjects. Using this cardiovascular tissue surrogate, the mRNA levels of the Finkel-Biskis-Jinkins osteosarcoma (FOS) gene in circulating monocytes were found to correlate with atherosclerosis severity in patients, and with HMG CoA reductase inhibitor (statin) therapy in normal subjects. The major finding of this investigation is discussed in relation to observations from other human atherosclerosis gene expression studies. These distinct studies converge to demonstrate the unequivocal importance of inflammation in atherosclerosis. Although the clinical utility of the specific findings remains open, the identification of similar genes by different investigations serves to validate their reports. They also provide us with insights into pathogenesis that may impact future translational applications. Diagnostic markers of inflammation and atherosclerosisBased on our current understanding of atherosclerosis, the pathogenesis of this leading cause of morbidity and mortality in westernized societies is best described by chronic vascular inflammation that starts early in life and exacerbates with aging (Glass and Witztum 2001, Hansson 2005). Multiple hereditary and environmental factors contribute to the initiation and progression of this disease (Lusis 2000). However, some well established clinical risk factors such as low density lipoprotein (LDL) and the metabolic syndrome (including obesity and insulin-resistance, diabetes) and basic factors such as angiotensin II all appear to promote oxidative stress and inflammation (Daugherty and Cassis 2004, Glass and Witztum 2001, Libby 2002. Though a number of molecules linked to inflammation have been proposed for use as atherosclerosis markers, C-reactive protein (CRP) has gained prominence because of its association with increased cardiovascular risk in clinical trials (Jain and Ridker 2005). Revealing insights into statins' mechanism of action, the recent clinical trial PROVE IT-TIMI 22 separated the cholesterol lowering and anti-inflammatory effects of statin therapy by demonstrating the independent and additive predictive values of serum cholesterol and CRP levels on cardiovascular events, respectively (Jain andRidker 2005, Ridker et al. 2005). A question that follows such fundamental observations is whether there exist other predictive markers that have equal or greater sensitivity and specificity. Th...

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Section: Concordance Of Transcriptional Studies Of Human Atherosclerosupporting

confidence: 90%

Genomic Analysis of Circulating Cells: A Window Into Atherosclerosis

Kang

Patino

Matoba

et al. 2006

Trends in Cardiovascular Medicine

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“…In addition to HT1080 cells, this suppression mechanism has been observed in human glioblastoma cells 7 and in the mouse. 8 In connective tissue cells, TGFb1-induced fibrosis in a variety of settings may also be attributed to Egr1. [9][10][11] Thus, TGFb1 appears to be a general effector of Egr1-dependent growth regulation.…”

Section: Tgfb1mentioning

confidence: 99%

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

Bar-On

Adamson

Calogero³

et al. 2005

Cancer Gene Ther

326

281

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Recent studies are reviewed indicating that the transcription factor early growth response-1 (Egr1) is a direct regulator of multiple tumor suppressors including TGFb1, PTEN, p53, and fibronectin. The downstream pathways of these factors display multiple nodes of interaction with each other, suggesting the existence of a functional network of suppressor factors that serve to maintain normal growth regulation and resist the emergence of transformed variants. Paradoxically, Egr1 is oncogenic in prostate cancer. In the majority of these cancers, PTEN or p53 is inactive. It is suggested that these defects in the suppressor network allow for the unopposed induction of TGFb1 and fibronectin, which favor transformation and survival of prostate tumor epithelial cells, and explain the role of Egr1 in prostate cancer. Egr1 is a novel and logical target for intervention by gene therapy methods, and targeting methods are discussed.

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“…This would be consistent with its known role in various biological processes involving neovascularization and/or angiogenesis. 56,57,73,74 In conclusion, our data show that expression of N1 EC can reprogram macrophages in such a unique way that they acquire the ability to significantly affect neighboring endothelial cells, most likely by producing several pro-or anti-angiogenic factors, thus leading to the development of vascular cavernous lesions and additional vascular patterning defects. Our data suggest a new molecular mechanism for the involvement of the Notch1 pathway in vascular diseases.…”

Section: The Pathogenesis Of the Liver Vascular Disease Of Cd4c/n1 Ecmentioning

confidence: 70%

Overexpression of Notch1 Ectodomain in Myeloid Cells Induces Vascular Malformations through a Paracrine Pathway

Calvo

Cool

et al. 2007

The American Journal of Pathology

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High-level expression of Egr-1 and Egr-1–inducible genes in mouse and human atherosclerosis

Cited by 273 publications

References 58 publications

Genomic Analysis of Circulating Cells: A Window Into Atherosclerosis

Genomic Analysis of Circulating Cells: A Window Into Atherosclerosis

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

Overexpression of Notch1 Ectodomain in Myeloid Cells Induces Vascular Malformations through a Paracrine Pathway

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