key: cord-0889891-qatf75rc authors: Khachigian, Levon M. title: Early Growth Response‐1, an Integrative Sensor in Cardiovascular and Inflammatory Disease date: 2021-11-10 journal: J Am Heart Assoc DOI: 10.1161/jaha.121.023539 sha: cd3a853064c0a4e18d84e6ac7cf310d108efb442 doc_id: 889891 cord_uid: qatf75rc Early growth response‐1 (Egr‐1) is a master regulator and transcriptional sensor in vascular dysfunction and disease. This article reviews recent developments in our understanding of the regulatory roles this zinc finger protein and product of an immediate‐early gene plays in a range of cardiovascular and inflammatory disorders. Egr‐1 can amplify pathologic signals from the extracellular environment by serving as a molecular conduit in the inducible expression of proliferative, migratory and proinflammatory genes driving disease progression. Strategies targeting Egr‐1 may provide therapeutic benefit in cardiovascular and inflammatory disorders. arly growth response-1 (Egr-1) is an immediateearly gene that resides on human chromosome 5q23-q31 and encodes a Cys 2 -His 2 type zinc finger transcription factor comprising 543 residues. The gene (also known as TIS8, 1 NGFI-A, 2 Krox-24, 3 ZIF-268, 4 and Egr1/EGR1 5 ) was cDNA cloned in the mid-1980s from cultured human lymphocytes activated with lectin and cycloheximide, given the name "G0S30" (G0 to G1 Switch Gene 30) and a partial sequence deposited in GenBank. 6 Rapid and transient induction typifies Egr-1 activation in diverse human cell types responding to a range of agonists and conditions. 7 Egr-1 is activated by serum, cytokines, growth factors, hormones, mechanical injury, endotoxin, hypoxia and shear stress, among other stimuli. The Egr-1 promoter contains multiple serum response elements that support serum response factor interactions with ternary complex factors (such as Elk-1 and SAP-1) that undergo phosphorylation by mitogen-activated protein kinases (Figure) . Inducible Egr-1 expression is reliant upon the activity of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase, p38 kinase, protein kinase A, protein kinase B and protein kinase C. Egr-1 interacts with recognition elements in promoter/enhancer regions of responsive genes, including platelet-derived growth factor (PDGF)-A, PDGF-B, PDGF-C, tissue factor, collagen, suppressor of cytokine signaling-1, colony-stimulating factor 1 receptor and Egr-1 itself. 8 Trizzino et al 9 linked Egr-1 with the transcriptional control of ≈1600 genes during macrophage development. Egr-1 physically interacts with multiple transcription and regulatory factors such as CREB-binding protein/ p300, nuclear factor-κB(NFκB) p65, p53, and YAP-1 and can modulate gene expression by displacing or competing with Sp1 at overlapping binding sites. 10 Egr-1 is also able to suppress inflammatory genes by indirect recruitment and association with the nucleosome remodeling and deacetylation corepressor complex causing deacetylation, thereby reducing chromatin accessibility. 9 Egr-1 undergoes negative regulation by two corepressors, NGFI-A binding protein (NAB) 1, and NAB2. Egr-1 and other family members, Egr-2 and Egr-3, can induce the expression of NAB2, creating a negative autoregulatory feedback loop. Egr-1 is subject to post-translational modification through acetylation, SUMOylation, ubiquitination and phosphorylation. For example, Vedantham et al 11 found Egr-1 hyperacetylation in hyperglycemia and induction of proinflammatory and prothrombotic signals by aldose reductase. Manente et al 12 reported that Egr-1 is SUMOylated and ubiquitinated in cells exposed to epidermal growth factor (EGF), and that this, together with proteasome mediated degradation, is enhanced by SUMO1/Ubc9 overexpression. Egr-1 also interacts with PRC8, a subunit of the proteasome core complex and undergoes multiubiquitination, destining it for proteolysis through the ubiquitin-dependent proteasome pathway. 13 While some of this work has been performed in nonvascular cell types, such processes may provide opportunities for therapeutic intervention in cardiovascular and inflammatory disease. Egr-1 is poorly expressed in the normal blood vessel wall but, when induced, can drive the expression of key growth factor and proinflammatory genes (e.g., PDGF-B, intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) impacting pathogenesis (Table) . For example, Egr-1 regulates atherosclerosis, 14 postangioplasty restenosis, 15 in-stent restenosis, 16 and vein graft stenosis. 17 Mice deficient in Egr-1 and apolipoprotein E have reduced atherosclerosis and vascular inflammation. 18 But how Egr-1 is controlled in the injured artery wall is not well understood. MicroRNAs are noncoding, single-stranded RNAs that can regulate gene expression by reducing levels of mRNA these target. We identified a micro-RNA targeting Egr-1 (miR-191) that suppresses smooth muscle cell (SMC) growth and intimal thickening after balloon catheter injury of carotid arteries. 19 Other mi-croRNAs targeting Egr-1 include miR-181, miR-183 and miR-150-5p. Vascular injury is able to acutely release endogenous growth factors such as fibroblast growth factor (FGF)-2, 20 which can activate Egr-1 gene expression. 21 A cocktail composed of VEGF-A, VEGF-D, and cyclic Arg-Gly-Asp peptide inhibits both Egr-1 and neointima formation after balloon injury. This was associated with increased endothelial nitric oxide synthase expression and accelerated reendothelialization. 22 SMC hypertrophy and vascular remodeling underpin hypertension, a process associated with angiotensin II. ERK is phosphorylated and Egr-1 is inducibly expressed in SMC exposed angiotensin II. Recent studies by Troung et al 23 46 Yamamoto et al 48 Khachigian Egr-1 in Cardiovascular and Inflammatory Disease phosphoinositide 3-kinase/Akt pathway and phosphorylation of histone deacetylase 5. Blockade of phosphoinositide 3-kinase/Akt using wortmannin/ SC66 or Akt siRNA inhibited angiotensin II-induced histone deacetylase 5 phosphorylation and its nuclear export. Moreover, depletion of histone deacetylase 5 or Egr-1 reduced SMC hypertrophy in response to angiotensin II. 23 Egr-1 expression activated by angiotensin II is negatively regulated by cAMP, suggesting a mechanism by which cAMP exerts vasculoprotective effects. The angiotensin II/ERK/Egr-1 axis is also controlled by stromal interaction molecule-1/Orai-1 proteins, which regulate intracellular calcium flux. Simo-Cheyou et al 24 found that pharmacologic inhibition of the inositol-3-phosphate receptor lowers angiotensin IIinduced levels of Egr-1 and intracellular calcium in SMC. Moreover, siRNA knockdown of either stromal interaction molecule-1 or Orai-1 reduced angiotensin II induction of Egr-1. Pharmacologic blockade of calmodulin and calmodulin kinase revealed that these effectors of calcium signaling also mediate angiotensin II induction of Egr-1. Egr-1 expression is regulated through Orai-1 channels that facilitate increased intracellular levels of Ca 2+ that bind calmodulin, which interacts with calcium-calmodulin-dependent protein kinase II and mediates ERK1/2 and CREB activation. Antenatal hypoxia, a common form of intrauterine stress, can adversely affect cardiovascular health later in life; however, the underlying mechanisms are incompletely understood. Xu et al 25 studied mechanisms of acquired vascular dysfunction in offspring caused by antenatal hypoxia and identified a role for Egr-1. Antenatal hypoxia upregulated angiotensin II type 1 receptor and hypomethylation-mediated activated transcription of Agtr1a (angiotensin II type 1 receptor-α subtype). Angiotensin II-angiotensin II type 1 receptor interaction increased protein kinase C (PKC)-ε Figure. Simplified representation of induction of early growth response-1 (Egr-1) and Egr-1dependent genes Transcription of Egr-1, an immediate-early gene encoding a zinc finger (ZNF) protein, is activated by a range of extracellular stimuli through interactions of serum response factor (SRF) with ternary complex factors (TCF), which undergo phosphorylation, in its promoter region. Egr-1 protein itself undergoes phosphorylation and physical interactions with other transcriptional regulators including NGFI-A binding protein (NAB), CREB-binding protein (CBP), yes-associated protein 1 (YAP-1), p53 and NFκB. Egr-1 binds to recognition elements in the promoter/enhancer regions of target genes and can displace or compete with Sp1. Examples of Egr-1-dependent genes impacting cell phenotype are provided in the figure. ERK denotes extracellular signal-regulated kinase; JNK, c-Jun N-terminal protein kinase; PKA, protein kinase A; PKB, protein kinase B; PKC, protein kinase C; SRE, serum response element; and UV, ultraviolet light. Egr-1 in Cardiovascular and Inflammatory Disease transcription by stimulating Egr-1 which was enriched at the PKC-ε promoter. Hypomethylation-dependent Agtr1a gene activation with downstream Egr-1 control of PKC-ε therefore may account for vascular hypercontractility in antenatal hypoxic offspring. 25 Tubulointerstitial fibrosis in diabetic kidney disease (DKD) can lead to chronic renal failure and involves epithelial-mesenchymal transition. Li et al 26 found that the antiaging factor Klotho can attenuate renal fibrosis in mice by inhibition of ERK1/2 signaling and suppression of Egr-1 activation. Overexpression of Klotho reduced Egr-1 expression whereas silencing Klotho increased Egr-1 levels, which was shut down with an ERK1/2 inhibitor. Hence, Klotho controls Egr-1 through ERK1/2 signaling, a novel mechanism in DKD progression. Ho et al 27 found that in patients with renal failure Egr-1 expression was increased in renal tubular cells, and used Egr-1 deficient mice to demonstrate that Egr-1 promotes renal inflammation and fibrosis. Egr-1 expression increased in kidneys of mice fed an adenine-rich diet that induced tubulointerstitial nephritis. Mice lacking Egr-1 were protected from renal failure, with reduced cytokine/chemokine expression in kidney, tubular injury, immune cell infiltration and fibrosis. Egr1 −/− mice with nephritis expressed less tumor necrosis factor-α (TNFα), macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 (MCP-1) than wild-type mice. 27 Since renal tissue was sourced from individuals with diabetes, it is unclear whether Egr-1 upregulation was attributable to diabetes or renal failure. Lipoxins are lipid-based mediators that control resolution of inflammatory disorders such as DKD. Brennan et al 28 found that lipoxin A 4 ameliorates diabetesinduced albuminuria, mesangial expansion and collagen deposition in a mouse DKD model. Lipoxin given 10 weeks after disease onset suppressed preexisting DKD and expression of known inflammatory mediators including TNF-α, interleukin-1β (IL-1β) and NFκB. Lipoxin A 4 also reduced levels of Egr-1 in kidney tissue. In cultured human renal epithelial cells, TNF-α induction of Egr-1 was inhibited by lipoxin A 4 while Egr-1 siRNA attenuated VCAM-1 and TNF-α expression in response to TNF-α. 28 The restricted repertoire of genes expressed by these immortalized cells limited the broader interpretation of these experiments. The data nonetheless suggest that lipoxins control transcriptional networks involving Egr-1 and can potentially reverse DKD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily that exert anti-inflammatory effects among other impacts on cell metabolism, differentiation, development and immune response. Nemeth et al 29 showed that the PPARγ agonist pioglitazone inhibits transforming growth factor-β (TGF-β)-driven renal fibrosis and its progression, by modulating profibrotic Egr-1 in TGF-β overexpressing transgenic mice. Glomerulosclerosis and tubulointerstitial damage induced by TGF-β were reduced by pioglitazone, which attenuated Egr-1 expression along with signal transducer and activator of transcription 3 and activator protein 1, suggesting that PPARγ agonists may be useful for treatment of chronic kidney disease with effects mediated through Egr-1. Xie et al 30 found that PPARγ expression in pulmonary artery SMC is inhibited by leptin, which stimulates proliferation, and that this involves ERK1/2 phosphorylation and induction of Egr-1. Inhibition of ERK1/2-Egr-1 signaling with pharmacologic inhibitors or siRNA, or activation of PPARγ with pioglitazone, inhibited leptin-inducible cell growth. Furthermore, in a CaCl 2 -induced model of abdominal aortic aneurysm comparing Egr-1-deficient bone marrow chimeric mice with controls reconstituted with wild-type bone marrow, no aneurysms were observed in mice lacking Egr-1. 31 Pioglitazone inhibited angiotensin II-inducible polycystic kidney disease 1 expression and Egr-1 occupancy of the polycystic kidney disease 1 promoter in cultured macrophages. This suggests the importance of both macrophages and Egr-1 in aneurysm formation and Egr-1 control by PPARγ. Rajaraman et al 32 investigated the relationship between advanced glycation end products (AGE), Egr-1, and gestational diabetes and found that levels of Egr-1, tissue factor, and soluble ICAM-1 were elevated in umbilical vein endothelial cells isolated from mothers with gestational diabetes. Egr-1 siRNA reduced tissue factor and ICAM-1 expression, confirming Egr-1 reliance by these genes. AGE elevate Egr-1 expression by way of a RAGE-PKC-βII-dependent ERK1/2 pathway, findings demonstrated in part using the macrocyclic bisindolylmaleimide, ruboxistaurin. This implicates the AGE/PKC-βII/ERK/Egr-1 axis in the pathogenesis of gestational diabetes. Atopic dermatitis is a common, chronic recurrent inflammatory skin disease currently with no cure. Yeo et al 33 studied AB1711, a novel small molecule targeting the DNA-binding domain of Egr-1 in the context of dermal inflammation. Topical application of 2,4-dinitrochlorobenzene to dorsal skin of mice resulted in severe atopic dermatitis, whereas mice lacking Egr-1 developed mild lesions that comprised myeloperoxidase-positive neutrophils, CD3 + T cells, and F4/80 + macrophages. AB1711 suppressed a range of TNF-α-inducible proinflammatory cytokine and chemokines including IL-1ß, interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 and ligand 5. In a separate group of mice in which 2,4-dinitrochlorobenzene was applied to ears, AB1711 lowered the number of scratching bouts stimulated by 2,4-dinitrochlorobenzene as effectively as dexamethazone. This study did not examine effects of AB1711 on angiogenesis nor investigate its pharmacodynamic profile. The data nonetheless indicate that Egr-1 is involved in the inflammatory microenvironment of skin and indicates the potential therapeutic clinical utility of AB1711 for other inflammatory disorders involving Egr-1. 33 Ischemia-reperfusion injury after myocardial infarction has adverse cardiovascular outcomes, and effective pharmacotherapeutic interventions are sought. DNAzymes targeting Egr-1 reduce myocardial infarct size in a rat model of ischemia-reperfusion injury accompanied by lower ICAM-1 expression and neutrophil infiltration in myocardium. Rayner et al 34 showed that Egr-1 knockdown following intracoronary delivery of DNAzymes in pigs at the time of reperfusion following acute myocardial ischemia suppressed markers of inflammation (namely, ICAM-1, tissue factor, interleukin-8, complement 3 and complement 3 receptor) and apoptosis. This strategy improved cardiac function through salvaged left ventricular myocardium, ejection fraction, and fractional area change. In a rat model of ischemia-reperfusion injury involving postconditioning, where multiple cycles of reperfusion/ ischemia is applied at the onset of reperfusion, Wang et al 35 found that postconditioning or pretreatment with curcumin reduced Egr-1 expression in myocardial nuclei and microvessels, attenuated inflammation (plasma TNF-α and IL-6 levels) and reduced infarct size. Remote ischemic preconditioning (RIPC) can also reduce myocardial injury following a heart attack, and this again involves Egr-1 modulation. Billah et al 36 used RIPC in a rat model of cardiac ischemia-reperfusion injury involving multiple cycles of hind-limb ligation and release. RIPC reduced Egr-1 expression and myocardial infarct size by activation of the Janus kinase-signal transducer and activator of transcription pathway. The cardioprotective effects of RIPC were abolished by Egr-1 DNAzymes injected in the hind limb. Acute lung injury (ALI) is typified by uncontrolled inflammation and macrophage infiltration. Wang and colleagues 37 showed that the allosteric mitogenactivated protein kinase inhibitor trametinib prevents lipopolysaccharide (LPS)-induced ALI in mice by reducing edema and neutrophil infiltration. Trametinib suppressed production of Egr-1 and a range of proinflammatory mediators including IL-1β, MCP-1 and TNF-α, and Egr-1-dependent genes including ICAM-1, tissue factor, and prostaglandin E synthase. Chen et al 38 found that ALI induced by LPS is blocked by trametinib through its inhibition of the mitogen-activated protein kinase-ERK-Egr-1 pathway. These findings suggest the potential clinical use of trametinib for ALI. Airway deposition of IgG immune complex is associated with ALI and sepsis. Yan et al 39 characterized an inverse relationship between PPARγ and Egr-1 expression. PPARγ was induced using its agonist rosiglitazone or adenoviral vectors, or suppressed with its antagonist GW9662 or shRNA. IgG immune complex stimulated Egr-1 mRNA levels in lung tissue by 13-fold, which was inhibited by airway administration of adenoviral PPARγ. IgG immune complex inducible TNF-α and MCP-1 expression was reduced by Egr-1 shRNA. Conversely, overexpression of Egr-1 increased TNF-α and MCP-1 promoter-dependent gene expression. PPARγ relieved the inflammatory response to IgG immune complex by reducing expression and transcriptional control by Egr-1 of a range of proinflammatory genes, including TNF-α and MCP-1. Treatment of mice with Egr-1 shRNA delivered by lentiviral vector reduced lung permeability and neutrophil recruitment to alveolar compartments. These findings suggest the PPARγ-Egr-1 axis is a targetable strategy for blockade of ALI or acute respiratory distress syndrome. 39 Akhter et al 40 identified an unknown population of sphingosine-1-phosphate (S1P) receptor 1 + endothelial cells during ALI critical for reestablishing the endothelial barrier. S1PR1 mediates ERK-dependent expression of Egr-1, which binds to and activates the sphingosine kinase 1 promoter causing S1P generation, vascular repair, and restoration of endothelial barrier function. Intravenous injection of S1PR1 + endothelial cells into conditional endothelial cell-S1PR1 deficient mice with injured lung vasculature resulted in integration of these cells within the intima restoring endothelial integrity. However, mechanisms of homing by these cells remain unresolved. Patients with pulmonary arterial hypertension (PAH) progressively develop neointimal lesions in small pulmonary arteries, causing elevated pulmonary vascular resistance and pressures, reducing cardiac output and heart failure. Egr-1 levels are elevated in human endstage PAH. Dickinson et al 41 found a pivotal role for Egr-1 in a flow-associated PAH model in rats in which Egr-1 DNAzymes reduced pulmonary vascular Egr-1 expression and the development of occlusive neointimal lesions. Egr-1 knockdown attenuated pulmonary vascular resistance, right ventricular systolic pressure and hypertrophy, levels of TGF-β, PDGF-B, IL-6, and p53, and increased apoptosis. Pioglitazone also inhibited neointimal lesion formation. 41 Van der Feen et al 42 examined Egr-1 expression in clinical pulmonary specimens with different forms and stages of PAH and found that Egr-1 expression is increased in PAH specifically with neointimal-type vascular remodeling. Similarly, in a murine model of pulmonary inflammation and fibrosis, Li et al 43 found that SARS coronavirus papain-like protease can stimulate macrophage infiltration and expression of Egr-1 and induction of TGF-β, thrombospondin-1 and profibrotic genes. Sepsis remains the major cause of mortality in hospital intensive care units and is associated with endothelial permeability and multiorgan dysfunction. Chen et al 44 showed that Egr-1 and ADAM10 levels positively correlate with severe sepsis in patients, with rs653765 GG carriers having higher Egr-1 mRNA levels than those with the AA or GA genotype. Egr-1 binds to and activates the ADAM10 promoter in an allele-dependent manner. Studies in a mouse endotoxemia (LPS) model showed that antisense Egr-1 oligonucleotides reduced host ADAM10 expression, proinflammatory cytokine secretion (TNF-α, IL-6 and IL-1β), adhesion molecule expression (ICAM-1 and VCAM-1), and improved survival. 44 Future studies should further delineate the therapeutic potential of targeting the Egr-1/ ADAM10 pathway in sepsis and the prognostic value of rs653765 polymorphisms. Egr-1 may also play a role in heart transplant rejection. Pivotal studies by Okada et al 45 demonstrated that Egr-1, together with PDGF-A, ICAM-1 and VCAM-1 are strongly expressed in cardiac allografts after transplantation, while Autieri et al 46 showed that Egr-1 expression may serve as a surrogate marker of cardiac allograft rejection, demonstrating a relationship between Egr-1 expression and rejection grade in endomyocardial biopsies. The success of allogeneic organ transplantation is limited by T-cell-mediated alloimmune reactions resulting in graft-versus-host disease. Peltier et al 47 recently reported that the long noncoding RNA Linc00402 is a regulator of T-cell alloimmunity following hematopoietic stem cell transplantation. Overexpression of Linc00402 in Jurkat cells increased ERK1/2 phosphorylation and stimulated expression of Egr-1, which can enhance T-cell activation and interleukin-2 production. Linc00402 increased in donor T cells from patients undergoing allogeneic heart transplantation and was reduced in those who developed acute graft-versushost disease. 47 Future studies should explore the therapeutic use of Linc00402 in allograft rejection or acute graft-versus-host disease and its effects on Egr-1. Ischemia-reperfusion injury is an important cause of morbidity and mortality after lung transplantation. In an orthotopic vascularized lung transplantation mouse model, Yamamoto et al 48 found that Egr-1 controls this process by regulating neutrophil infiltration. Immunohistochemistry revealed normal lungs showing no staining of Egr-1 whereas transplanted lungs expressed Egr-1 within an hour of reperfusion in pulmonary artery endothelial cells and neutrophils. Egr-1 deficiency improved pulmonary graft function and reduced neutrophil infiltration. Egr-1 may therefore be a useful target for lowering lung ischemia-reperfusion injury. However, the specific Egr-1-dependent factors controlling neutrophil infiltration remain to be elucidated. Egr-1 stimulates angiogenesis in a range of settings including wound healing, corneal neovascularization, and tumor angiogenesis. 49 Adenoviral delivery of a form of Egr-1 unable to be suppressed by NAB can increase expression of FGF-2, PDGF-A, PDGF-B, insulin-like growth factor II, and TGF-ß and tissue perfusion in a mouse model of hindlimb ischemia. 50 Even though Egr-1 was described as a phosphoprotein when initially characterized 3 decades ago, actual residue(s) phosphorylated in Egr-1 remained elusive until we identified Ser26, which is highly conserved in Egr-1 and unique to Egr-1 in the Egr family. Ser26 is phosphorylated by ERK. 51 To establish the functional significance of Ser26 we devised a CRISPR/Cas9 strategy to introduce a homozygous Ser26>Ala mutation into Egr-1 in human vascular endothelial cells. 52 Cells bearing this mutation proliferated and migrated slower than those with wild-type Egr-1. Mutant cells formed fewer networks on solubilized basement membrane preparations and increased expression of vascular endothelial cadherin, which controls endothelial adhesion, permeability, and angiogenesis, and underwent apoptosis. The phenotypic effects of this mutation were comparable to deletion of Egr-1 itself, thereby underlining the importance of Ser26 to the function of Egr-1. Egr-1 also regulates endothelial progenitor cells, which differentiate into mature endothelial cells and regulate neovascularization in conditions such as myocardial ischemia. Ye and colleagues 53 showed that the androgen dihydrotestosterone can promote the migration and proangiogenic properties of endothelial progenitor cells. Egr-1 knockdown inhibited endothelial progenitor cell migration stimulated by dihydrotestosterone, suggesting that androgen regulates endothelial progenitor cell function through Egr-1 signaling. 53 Egr-1 in Cardiovascular and Inflammatory Disease As an immediate-early gene that responds rapidly and transiently to a wide range of extracellular stimuli, Egr-1 integrates changes in the local microenvironment with programs of inducible gene expression. While it is known that Egr-1 undergoes posttranslational modification and interacts with a range of transcription factors, our understanding of mechanisms with which Egr-1 regulates transcription and drives the pathogenesis of disease is far from complete. Future studies should provide a more detailed dissection of the mechanistic roles played by Egr-1 in vascular dysfunction and inflammatory disease and develop new strategies exploiting this knowledge. Cloning of tetradecanoyl phorbol ester-induced 'primary response' sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc finger" sequences A zinc-finger encoding gene corregulated with c-Fos during growth and differentiation and after depolarization A set of human putative lymphocyte g0/g1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells Phosphorylation and acetylation of histone h3 and autoregulation by early growth response 1 mediate interleukin 1beta induction of early growth response 1 transcription Egr1 is a gatekeeper of inflammatory enhancers in human macrophages Interplay of SP1 and Egr-1 in the proximal PDGF-a promoter in cultured vascular endothelial cells Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals Coordinated sumoylation and ubiquitination modulate EGF induced EGR1 expression and stability Regulation of Egr-1 by association with the proteasome component C8 High-level expression of Egr-1 and Egr-1-inducible genes in mouse and human atherosclerosis New DNA enzyme targeting egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth factor injury Catalytic oligodeoxynucleotides define a key regulatory role for early growth response factor-1 in the porcine model of coronary in-stent restenosis Early growth response protein 1 promotes restenosis by upregulating intercellular adhesion molecule-1 in vein graft Early growth response-1 promotes atherogenesis: mice deficient in early growth response-1 and apolipoprotein e display decreased atherosclerosis and vascular inflammation MicroRNA miR-191 targets the zinc finger transcription factor Egr-1 and suppresses intimal thickening after carotid injury Acute local release of fibroblast growth factor-2 but not transforming growth factor-beta1 following coronary stenting Early growth response factor-1 induction by injury is triggered by release and paracrine activation by fibroblast growth factor-2 Inhibition of intimal thickening after vascular injury with a cocktail of vascular endothelial growth factor and cyclic Arg-Gly-Asp peptide Angiotensin IIinduced histone deacetylase 5 phosphorylation, nuclear export, and Egr-1 expression are mediated by Akt pathway in a10 vascular smooth muscle cells STIM-1 and Orai-1 channel mediate angiotensin-II-induced expression of Egr-1 in vascular smooth muscle cells DNA methylation-reprogrammed ANG II (angiotensin II) type 1 receptor-early growth response gene 1-protein kinase C epsilon axis underlies vascular hypercontractility in antenatal hypoxic Khachigian Egr-1 in Cardiovascular and Inflammatory Disease offspring Klotho prevents epithelial-mesenchymal transition through Egr-1 downregulation in diabetic kidney disease Egr-1 deficiency protects from renal inflammation and fibrosis The PPARgamma agonist pioglitazone prevents TGF-beta induced renal fibrosis by repressing Egr-1 and STAT3 Egr-1 mediates leptin-induced PPARgamma reduction and proliferation of pulmonary artery smooth muscle cells Pioglitazone identifies a new target for aneurysm treatment: Role of Egr1 in an experimental murine model of aortic aneurysm Hyperglycaemia cause vascular inflammation through advanced glycation end products/early growth response-1 axis in gestational diabetes mellitus Disrupting the DNA binding of Egr-1 with a smallmolecule inhibitor ameliorates 2,4-dinitrochlorobenzene-induced skin inflammation Selective inhibition of Egr-1 using catalytic oligonucleotides reduces myocardial injury and improves lv systolic function in a preclinical model of myocardial infarction Attenuation of inflammatory response and reduction in infarct size by postconditioning are associated with downregulation of early growth response 1 during reperfusion in rat heart Egr-1 functions as a master switch regulator of remote ischemic preconditioning-induced cardioprotection The extracellular matrix protein mindin attenuates colon cancer progression by blocking angiogenesis via Egr-1-mediated regulation Trametinib alleviates lipopolysaccharide-induced acute lung injury by inhibiting the MEK-ERK-Egr-1 pathway The crucial role of PPARgamma-egr-1-pro-inflammatory mediators axis in igg immune complex-induced acute lung injury Programming to s1pr1(+) endothelial cells promote restoration of vascular integrity A critical role for Egr-1 during vascular remodelling in pulmonary arterial hypertension Egr-1 identifies neointimal remodeling and relates to progression in human pulmonary arterial hypertension SARS coronavirus papain-like protease induces Egr-1-dependent upregulation of TGF-beta1 via ROS/P38 MAPK/STAT3 pathway A functional polymorphism-mediated disruption of EGR1/ADAM10 pathway confers the risk of sepsis progression Transcriptional control of cardiac allograft vasculopathy by early growth response gene-1 (Egr-1) Early growth responsive gene (Egr)-1 expression correlates with cardiac allograft rejection RNA-seq of human T cells after hematopoietic stem cell transplantation identifies linc00402 as a regulator of T cell alloimmunity Early growth response-1 plays an important role in ischemia-reperfusion injury in lung transplants by regulating polymorphonuclear neutrophil infiltration Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth Adenoviral-mediated delivery of early growth response factor-1 gene increases tissue perfusion in a murine model of hindlimb ischemia Extracellular signal-regulated kinase-1 phosphorylates early growth response-1 at serine 26 Serine 26 in early growth response-1 is critical for endothelial proliferation, migration, and network formation Androgen modulates functions of endothelial progenitor cells through activated Egr1 signaling The author regrets that, because of space constraints, other seminal studies in the field could not be cited. This work was supported by funding from the National Health and Medical Research Council and National Heart Foundation of Australia. None.