- Open Access
Alterations in transcriptional responses associated with vascular aging
Journal of Inflammation volume 6, Article number: 16 (2009)
Vascular aging is an independent risk factor for cardiovascular disease that can occur in the absence of other traditional risk factors. Inflammation is a hallmark of vascular aging that ultimately leads to structural changes in the vessel wall including an increase in medial thickness and perivascular fibrosis. Several classes of transcription factors have been identified that participate in the regulation of cellular responses associated with vascular aging. Nuclear factor (NF)-κB is the prototypic example of a transcriptional activator in the setting of inflammation, being activated in response to multiple inflammatory mediators including pro-inflammatory cytokines and bacterial endotoxin. In contrast, the activation of the nuclear hormone receptor and transcription factor peroxisome proliferator-activated receptor-alpha (PPAR-α) results in its translocation from the cell surface to the nucleus where it exerts anti-inflammatory effects. Vascular aging is also associated with endothelial dysfunction. One important repair mechanism for improving endothelial function is the recruitment of endothelial progenitor cells (EPCs). In the setting of aging the number of EPCs diminishes which has been linked to a decrease in the activity and/or expression of the transcription factor hypoxia inducible factor (HIF)-1 alpha. A change in the balance of the activity of pro-inflammatory transcription factors versus those that inhibit inflammation likely contributes to the process of vascular aging. The purpose of this review is to summarize our current knowledge of these age-related changes in transcriptional responses, and to discuss the therapeutic potential of targeting some of these factors.
Epidemiological studies strongly support that vascular aging, which is accompanied by increased arterial stiffness, is an independent risk factor for cardiovascular morbidity and mortality [1–4]. Arterial stiffness is also frequently associated with the presence or the development of hypertension [5, 6]. Whether an increase in arterial stiffness always precedes the onset of hypertension has not been determined. Although the precise molecular mechanisms underlying arterial aging have not been elucidated, inflammation appears to be a central component [7–9]. Some of the mediators of this inflammatory response include pro-inflammatory cytokines such as tumor necrosis alpha (TNF-α), transforming growth factor-beta (TGF-β), and angiotensin II (Ang II). The focus of this article is to review some of the transcriptional mediators that are responsible for activating critical genes involved in the initiation and propagation of vascular aging (Table 1).
NF-κB is known as the prototypic transcriptional mediator of inflammation. Under non-inflammatory conditions the heterdimeric Rel domain subunits, p50 and p65, of NF-κB are constitutively expressed but remain inactivated in the cytoplasm bound to the inhibitory protein Iκ-B. In response to inflammation Iκ-B is degraded allowing p50 and p65 to form NF-κB that can now freely translocate to the nucleus . It was recently demonstrated that not only the expression but the activity of NF-κB is up-regulated during the process of aging [11, 12]. The expression and activity of NF-κB was evaluated in fibroblasts from patients with ages ranging from 22 to 92 years of age. Over time there was a significant increase in the activity of NF-κB and the expression of inflammatory genes.
During the process of vascular aging there is a similar increase in NF-κB expression and activity in vascular smooth muscle cells and endothelial cells. This has been attributed to a variety of different mechanisms . First, there is an increase in the levels of circulating cytokines, and in particular TNF-α during the process of aging. Second, vascular aging is associated with the increased production of reactive oxygen species (ROS), and in particular mitochondrial-derived H2O2 due to age-related mitochondrial dysfunction [12, 14, 15]. In the vascular endothelium age related increases in the expression of NF-κB are associated with increased expression of monocyte chemoattractant protein 1 (MCP-1) and a reduction in endothelium-dependent dilation . Similarly the activity and response of NF-κB to pro-inflammatory cytokines was enhanced in aged compared to young vascular smooth muscle cells and was associated with an augmentation of the induction of ICAM-1 and inducible nitric oxide synthase (NOS2) genes .
Hypoxia Inducible Factor-1 alpha (HIF-1α)
HIF-1α is a member of the transcription factor family and has been shown to be a critical regulator of neovascularization . HIF-1α is activated in the setting of hypoxia and promotes the expression of vascular endothelial growth factor (VEGF) . In the setting of myocardial ischemia or infarction the activation of HIF-1α promotes local angiogenesis through the expression of VEGF. In addition HIF-1α can induce the expression of stromal cell-derived factor-1 (SDF-1) . SDF-1 enhances the recruitment of endothelial progenitor cells (EPCs) in the setting of tissue injury or ischemia. One of the hallmarks of vascular aging is endothelial dysfunction. EPCs can promote the repair of dysfunctional or damaged endothelium. Recent studies suggest that the levels and activity of HIF-1α diminish with aging and thereby leads to reduced levels of SDF-1 [21, 22]. The results of these studies suggest that both local proliferation of endothelial cells by VEGF in the setting of ischemia, and the recruitment of EPCs to promote neovascularization or repair damaged endothelium are diminished with aging.
ETS factor family
The ETS factors are a family of transcription factors that share a highly conserved DNA binding domain (Ets domain). ETS factors are involved in regulating a wide variety of biological processes including normal development and differentiation . Until recently, very little was known about a role for ETS factors in regulating vascular inflammation. Over the past few years several studies have been completed that support a role for several ETS family members in the regulation of vascular inflammation, including endothelial activation in response to inflammatory mediators, the recruitment of inflammatory cells to the vessel wall, and proliferation and migration of vascular smooth muscle cells. We and others have observed that Ets-1 is induced in VSMC and endothelial cells in response to a variety of stimuli including Angiotensin II (Ang II), PDGF-BB, thrombin, interleukin-1 beta (IL-1β), and tumor necrosis alpha (TNF-α) [24–30]. Target genes identified to be downstream of Ets-1 in the setting of acute vascular inflammation include the chemokine MCP-1 and the adhesion molecule VCAM-1. Systemic administration of the vasoactive peptide Ang II via continuous infusion is not only associated with increases in blood pressure but also promotes the recruitment of inflammatory cells, including T cells and monocytic cells, to the vessel wall. The influx of inflammatory cells in response to Ang II is markedly diminished in Ets-1 deficient mice compared to littermate controls. One of the major mediators of vascular inflammation within the vessel wall is ROS. Ang II, for example, promotes the generation of superoxide anions in VSMC largely via the activity of NADPH oxidases, that can be converted to hydrogen peroxide by superoxide dismutase . Reactive oxygen species, and in particular hydrogen peroxide, can also stimulate Ets-1 expression . Ets-1 functions synergistically with the transcription factor Sp1 to regulate the expression of the PDGF receptor in an ROS-dependent manner. Ets-1 and Sp1 are enriched in VSMC found in human atherosclerotic lesions that express increased levels of the PDGF receptor.
The tumor suppressor molecule p16INK4a is a principal mediator of cellular senescence [33, 34]. Increased levels of p16INK4a have been detected in a number of different cell types associated with aging including vascular smooth muscle cells . The molecular mechanisms by which p16INK4a is regulated have not been fully elucidated, however at the transcriptional level it has recently been shown that Ets-1 is a critical factor in determining expression levels of p16INK4a in a number of cells and tissues during the process of aging . The age related increases in the expression of Ets-1 and p16INK4a are diminished by caloric restriction that is associated with weight gain. Administration of resveratrol, a natural atoxic phytoestrogen, to mice, mimics the transcriptional effects of caloric restriction . Resveratrol is an activator of sirtuins (SIRT1). Sirtuins are a family of NAD+-dependent deacetylases that can inhibit cell senescence. Resveratrol has been shown to reduce the levels of p16INK4a through activation of SIRT1 . The administration of resveratrol to mice, prevented age related reductions in endothelial function . Resveratrol is a potent inhibitor of NF-κB activation in endothelial cells . Similarly in obese mice, that exhibit a more rapid decline in vascular function that is associated with a pro-inflammatory state, administration of resveratrol reduced the obesity related endothelial dysfunction, that was at least in part related to a reduction in the generation of ROS .
ERG is an ETS family member that has been shown to contribute to the regulation of a number of endothelial-restricted genes including VE-cadherin, vWF, and angiopoietin-2 [40–42]. ERG is markedly downregulated in human endothelial cells in response to TNF-α. We have recently demonstrated that ERG functions as a suppressor of EC activation . Suppression of ERG using siRNA results in an increase in neutrophil attachment that is dependent on increased expression of interleukin-8 by endothelial cells. A significant number of genes that are up or down regulated by ERG suppression in endothelial cells overlap with genes that are similarly up or down regulated by TNF-α.
More recently selected transcription factors have been identified that exhibit anti-inflammatory properties and can modulate the initial cascade of genes induced in response to inflammatory stimuli. For example, the PPAR (peroxisome proliferators-activated receptors) nuclear receptors are transcription factors expressed in EC, VSMC, and monocytic cells. Activation of PPARα and PPARγ receptors are associated with favorable effects on lipid metabolism and insulin sensitivity that are also beneficial with regard to limiting the development of atherosclerosis . Binding of PPAR agonists to their cognate receptors is also associated with anti-inflammatory effects. Activation of the PPARγ pathway, for example, can inhibit the activity of the transcription factors AP-1 and NF-κB in response to pro-inflammatory cytokines such as TNF-α in endothelial cells . Activation of PPARγ also inhibits the process of vascular aging in rats [46, 47]. For example, the administration of the PPARγ agonist 2,4-thiazolidinedione (2,4-TZD) to rats of varying ages was associated with a reduction in the activity of NF-κB, pro-inflammatory cytokines, NOS2, and vascular cell adhesion molecule-1 (VCAM-1) in the kidney. The upregulation of NF-κB and associated inflammatory genes in the absence of treatment is an aged related phenomenon.
Targeting transcription factors
The elucidation of the critical transcriptional factors that regulate vascular inflammation may therefore not only advance our basic understanding of the molecular mechanisms of vascular inflammation but may also provide novel therapeutic targets for drug discovery. Historically, transcription factors have not been viewed as good targets for drug therapy, with the exception of nuclear hormone receptors that often reside on the cell surface and are activated by ligands that promote their transfer into nucleus where they function as transcription factors and bind to specific gene targets. One approach that has been used to target transcription factors in vivo is through the development of membrane permeable peptides that can competitively inhibit the binding of the transcription factors to the DNA. This approach was used to block the function of the ETS factor ELF-1 to inhibit the expression of the endothelial restricted genes Tie2 and endothelial nitric oxide synthase (eNOS) and block tumor angiogenesis in vivo . A similar approach was used in vivo to block the activity of Ets-1 and inhibit the generation of ROS, induction of inflammatory genes, and favorably effect vascular remodeling in response to Ang II infusion in mice over two weeks . The ability to identify small molecules that specifically block transcription factors that are not ligand-dependent has recently demonstrated . Although only a few transcription factors have been targeted in this way, and no drugs, with the exception of those targeting the nuclear hormone receptors, are currently available to block these factors, several companies are actively pursuing these factors as therapeutic targets.
Breithaupt-Grogler K, Belz GG: Epidemiology of the arterial stiffness. Pathol Biol (Paris). 1999, 47: 604-613.
Benetos A, Waeber B, Izzo J, Mitchell G, Resnick L, Asmar R, Safar M: Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications. Am J Hypertens. 2002, 15: 1101-1108. 10.1016/S0895-7061(02)03029-7.
Wang X, Keith JC, Struthers AD, Feuerstein GZ: Assessment of arterial stiffness, a translational medicine biomarker system for evaluation of vascular risk. Cardiovasc Ther. 2008, 26: 214-223. 10.1111/j.1755-5922.2008.00051.x.
Najjar SS, Scuteri A, Lakatta EG: Arterial aging: is it an immutable cardiovascular risk factor?. Hypertension. 2005, 46: 454-462. 10.1161/01.HYP.0000177474.06749.98.
Lekakis JP, Zakopoulos NA, Protogerou AD, Papaioannou TG, Kotsis VT, Pitiriga V, Tsitsirikos MD, Stamatelopoulos KS, Papamichael CM, Mavrikakis ME: Arterial stiffness assessed by pulse wave analysis in essential hypertension: relation to 24-h blood pressure profile. Int J Cardiol. 2005, 102: 391-395. 10.1016/j.ijcard.2004.04.014.
Safar H, Chahwakilian A, Boudali Y, Debray-Meignan S, Safar M, Blacher J: Arterial stiffness, isolated systolic hypertension, and cardiovascular risk in the elderly. Am J Geriatr Cardiol. 2006, 15: 178-182. 10.1111/j.1076-7460.2006.04794.x.
Mahmud A, Feely J: Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension. 2005, 46: 1118-1122. 10.1161/01.HYP.0000185463.27209.b0.
Wang M, Zhang J, Jiang LQ, Spinetti G, Pintus G, Monticone R, Kolodgie FD, Virmani R, Lakatta EG: Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension. 2007, 50: 219-227. 10.1161/HYPERTENSIONAHA.107.089409.
Pepe S, Lakatta EG: Aging hearts and vessels: masters of adaptation and survival. Cardiovasc Res. 2005, 66: 190-193. 10.1016/j.cardiores.2005.03.004.
Baeuerle PA, Baltimore D: NF-kappa B: ten years after. Cell. 1996, 87: 13-20. 10.1016/S0092-8674(00)81318-5.
Kriete A, Mayo KL: Atypical pathways of NF-kappaB activation and aging. Exp Gerontol. 2009, 44: 250-5. 10.1016/j.exger.2008.12.005.
Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K, Csiszar A: Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol. 2007, 293: H37-47. 10.1152/ajpheart.01346.2006.
Csiszar A, Wang M, Lakatta EG, Ungvari Z: Inflammation and endothelial dysfunction during aging: role of NF-kappaB. J Appl Physiol. 2008, 105: 1333-1341. 10.1152/japplphysiol.90470.2008.
Kriete A, Mayo KL, Yalamanchili N, Beggs W, Bender P, Kari C, Rodeck U: Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity. Immun Ageing. 2008, 5: 5-10.1186/1742-4933-5-5.
Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z: Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Am J Pathol. 2007, 170: 388-398. 10.2353/ajpath.2007.060708.
Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, Seals DR: Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res. 2007, 100: 1659-1666. 10.1161/01.RES.0000269183.13937.e8.
Yan ZQ, Sirsjo A, Bochaton-Piallat ML, Gabbiani G, Hansson GK: Augmented expression of inducible NO synthase in vascular smooth muscle cells during aging is associated with enhanced NF-kappaB activation. Arterioscler Thromb Vasc Biol. 1999, 19: 2854-2862.
Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995, 92: 5510-5514. 10.1073/pnas.92.12.5510.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996, 16: 4604-4613.
Karshovska E, Zernecke A, Sevilmis G, Millet A, Hristov M, Cohen CD, Schmid H, Krotz F, Sohn HY, Klauss V, Weber C, Schober A: Expression of HIF-1alpha in injured arteries controls SDF-1alpha mediated neointima formation in apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol. 2007, 27: 2540-2547. 10.1161/ATVBAHA.107.151050.
Loh SA, Chang EI, Galvez MG, Thangarajah H, El-ftesi S, Vial IN, Lin DA, Gurtner GC: SDF-1 alpha expression during wound healing in the aged is HIF dependent. Plast Reconstr Surg. 2009, 123: 65S-75S. 10.1097/PRS.0b013e318191bdf4.
Hoenig MR, Bianchi C, Rosenzweig A, Sellke FW: Decreased vascular repair and neovascularization with ageing: mechanisms and clinical relevance with an emphasis on hypoxia-inducible factor-1. Curr Mol Med. 2008, 8: 754-767. 10.2174/156652408786733685.
Wasylyk B, Hahn SL, Giovane A: The Ets family of transcription factors. Eur J Biochem. 1993, 211: 7-18. 10.1111/j.1432-1033.1993.tb19864.x.
Hultgardh-Nilsson A, Cercek B, Wang JW, Naito S, Lovdahl C, Sharifi B, Forrester JS, Fagin JA: Regulated expression of the ets-1 transcription factor in vascular smooth muscle cells in vivo and in vitro. Circ Res. 1996, 78: 589-595.
Goetze S, Kintscher U, Kaneshiro K, Meehan WP, Collins A, Fleck E, Hsueh WA, Law RE: TNFalpha induces expression of transcription factors c-fos, Egr-1, and Ets-1 in vascular lesions through extracellular signal-regulated kinases 1/2. Atherosclerosis. 2001, 159: 93-101. 10.1016/S0021-9150(01)00497-X.
Naito S, Shimizu S, Maeda S, Wang J, Paul R, Fagin JA: Ets-1 is an early response gene activated by ET-1 and PDGF-BB in vascular smooth muscle cells. Am J Physiol. 1998, 274: C472-480.
Zhan Y, Brown C, Maynard E, Anshelevich A, Ni W, Ho IC, Oettgen P: Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling. J Clin Invest. 2005, 115: 2508-2516. 10.1172/JCI24403.
Redlich K, Kiener HP, Schett G, Tohidast-Akrad M, Selzer E, Radda I, Stummvoll GH, Steiner CW, Groger M, Bitzan P, Zenz P, Smolen JS, Steiner G: Overexpression of transcription factor Ets-1 in rheumatoid arthritis synovial membrane: regulation of expression and activation by interleukin-1 and tumor necrosis factor alpha. Arthritis Rheum. 2001, 44: 266-274. 10.1002/1529-0131(200102)44:2<266::AID-ANR43>3.0.CO;2-G.
Liu AY, Corey E, Vessella RL, Lange PH, True LD, Huang GM, Nelson PS, Hood L: Identification of differentially expressed prostate genes: increased expression of transcription factor ETS-2 in prostate cancer. Prostate. 1997, 30: 145-153. 10.1002/(SICI)1097-0045(19970215)30:3<145::AID-PROS1>3.0.CO;2-L.
Santiago FS, Khachigian LM: Ets-1 stimulates platelet-derived growth factor A-chain gene transcription and vascular smooth muscle cell growth via cooperative interactions with Sp1. Circ Res. 2004, 95: 479-487. 10.1161/01.RES.0000141135.36279.67.
Griendling KK, Sorescu D, Ushio-Fukai M: NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000, 86: 494-501.
Bonello MR, Bobryshev YV, Khachigian LM: Peroxide-inducible Ets-1 mediates platelet-derived growth factor receptor-alpha gene transcription in vascular smooth muscle cells. Am J Pathol. 2005, 167: 1149-1159.
Palmero I, McConnell B, Parry D, Brookes S, Hara E, Bates S, Jat P, Peters G: Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status. Oncogene. 1997, 15: 495-503. 10.1038/sj.onc.1201212.
Baker DJ, Perez-Terzic C, Jin F, Pitel K, Niederlander NJ, Jeganathan K, Yamada S, Reyes S, Rowe L, Hiddinga HJ, Eberhardt NL, Terzic A, van Deursen JM: Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008, 10: 825-836. 10.1038/ncb1744.
Rodriguez-Menocal L, Pham SM, Mateu D, St-Pierre M, Wei Y, Pestana I, Aitouche A, Vazquez-Padron RI: Aging increases p16Ink4a expression in vascular smooth muscle cells. BiosciRep. 2009,
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE: Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004, 114: 1299-1307.
Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R: Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008, 8: 157-168. 10.1016/j.cmet.2008.06.011.
Huang J, Gan Q, Han L, Li J, Zhang H, Sun Y, Zhang Z, Tong T: SIRT1 overexpression antagonizes cellular senescence with activated ERK/S6k1 signaling in human diploid fibroblasts. PLoS ONE. 2008, 3: e1710-10.1371/journal.pone.0001710.
Csiszar A, Smith K, Labinskyy N, Orosz Z, Rivera A, Ungvari Z: Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition. Am J Physiol Heart Circ Physiol. 2006, 291: H1694-1699. 10.1152/ajpheart.00340.2006.
Hasegawa Y, Abe M, Yamazaki T, Niizeki O, Shiiba K, Sasaki I, Sato Y: Transcriptional regulation of human angiopoietin-2 by transcription factor Ets-1. Biochem Biophys Res Commun. 2004, 316: 52-58. 10.1016/j.bbrc.2004.02.019.
Schwachtgen JL, Janel N, Barek L, Duterque-Coquillaud M, Ghysdael J, Meyer D, Kerbiriou-Nabias D: Ets transcription factors bind and transactivate the core promoter of the von Willebrand factor gene. Oncogene. 1997, 15: 3091-3102. 10.1038/sj.onc.1201502.
Birdsey GM, Dryden NH, Amsellem V, Gebhardt F, Sahnan K, Haskard DO, Dejana E, Mason JC, Randi AM: Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin. Blood. 2008, 111: 3498-3506. 10.1182/blood-2007-08-105346.
Yuan L, Nikolova-Krstevski V, Zhan Y, Kondo M, Bhasin M, Varghese L, Yano K, Carman CV, Aird WC, Oettgen P: Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene. Circ Res. 2009, 104: 1049-1057. 10.1161/CIRCRESAHA.108.190751.
Plutzky J: Medicine. PPARs as therapeutic targets: reverse cardiology?. Science. 2003, 302: 406-407. 10.1126/science.1091172.
Wang N, Verna L, Chen NG, Chen J, Li H, Forman BM, Stemerman MB: Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem. 2002, 277: 34176-34181. 10.1074/jbc.M203436200.
Sung B, Park S, Yu BP, Chung HY: Modulation of PPAR in aging, inflammation, and calorie restriction. J Gerontol A Biol Sci Med Sci. 2004, 59: 997-1006.
Sung B, Park S, Yu BP, Chung HY: Amelioration of age-related inflammation and oxidative stress by PPARgamma activator: suppression of NF-kappaB by 2,4-thiazolidinedione. Exp Gerontol. 2006, 41: 590-599. 10.1016/j.exger.2006.04.005.
Huang X, Brown C, Ni W, Maynard E, Rigby AC, Oettgen P: Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. Blood. 2006, 107: 3153-3160. 10.1182/blood-2005-08-3206.
Ni W, Zhan Y, He H, Maynard E, Balschi JA, Oettgen P: Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47phox Gene Expression in Response to Angiotensin II. Circ Res. 2007, 101: 985-94. 10.1161/CIRCRESAHA.107.152439.
Koehler AN, Shamji AF, Schreiber SL: Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. J Am Chem Soc. 2003, 125: 8420-8421. 10.1021/ja0352698.
This work was supported by NIH grant P01 HL76540 (PO), RO1 HL082717 (PO), the AHA Established Investigator Award EIA0740012 (PO), and T32 training grant HL07374-26 (YZ)
The authors declare that they have no competing interests.
YZ contributed to the writing of this manuscript. LJ contributed to the writing of this manuscript. PO contributed to the writing of this manuscript. All authors read and approved the final manuscript.
About this article
Cite this article
Zhan, Y., Yuan, L. & Oettgen, P. Alterations in transcriptional responses associated with vascular aging. J Inflamm 6, 16 (2009). https://doi.org/10.1186/1476-9255-6-16
- Vascular Endothelial Growth Factor
- Vascular Smooth Muscle Cell
- Arterial Stiffness
- Vascular Inflammation