Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study

Authors: Giorgio Aquila, Cinzia Fortini, Antonio Pannuti, Serena Delbue, Micaela Pannella, Marco Bruno Morelli, Cristiana Caliceti, Fausto Castriota, Monica de Mattei, Alessia Ongaro, Agnese Pellati, Pasquale Ferrante, Lucio Miele, Luigi Tavazzi, Roberto Ferrari, Paola Rizzo, Alberto Cremonesi

Published in: Journal of Translational Medicine | Issue 1/2017

Login to get access

Abstract

Background

The lack of early diagnosis, progression markers and effective pharmacological treatment has dramatic unfavourable effects on clinical outcomes in patients with peripheral artery disease (PAD). Addressing these issues will require dissecting the molecular mechanisms underlying this disease. We sought to characterize the Notch signaling and atherosclerosis relevant markers in lesions from femoral arteries of symptomatic PAD patients.

Methods

Plaque material from the common femoral, superficial femoral or popliteal arteries of 20 patients was removed by directional atherectomy. RNA was obtained from 9 out of 20 samples and analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).

Results

We detected expression of Notch ligands Delta-like 4 (Dll4) and Jagged1 (Jag1), of Notch target genes Hes1, Hey1, Hey2, HeyL and of markers of plaque inflammation and stability such as vascular cell adhesion molecule 1 (VCAM1), smooth muscle 22 (SM22), cyclooxygenase 2 (COX2), Bcl2, CD68 and miRNAs 21-5p, 125a-5p, 126-5p,146-5p, 155-5p, 424-5p. We found an “inflamed plaque” gene expression profile characterized by high Dll4 associated to medium/high CD68, COX2, VCAM1, Hes1, miR126-5p, miR146a-5p, miR155-5p, miR424-5p and low Jag1, SM22, Bcl2, Hey2, HeyL, miR125a-5p (2/9 patients) and a “stable plaque” profile characterized by high Jag1 associated to medium/high Hey2, HeyL, SM22, Bcl2, miR125a and low Dll4, CD68, COX2, VCAM1, miR126-5p, miR146a-5p, miR155-5p, miR424-5p (3/9 patients). The remaining patients (4/9) showed a plaque profile with intermediate characteristics.

Conclusions

This study reveals the existence of a gene signature associated to Notch activation by specific ligands that could be predictive of PAD progression.
Appendix
Available only for authorised users
Literature
1.
Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329–40.CrossRefPubMed
2.
Armstrong EJ, Sab S, Singh GD, Lim W, Yeo KK, Waldo SW, Patel M, Reeves R, MacGregor JS, Low RI, Shunk KA, Mahmud E, Rogers JH. Predictors and outcomes of recurrent stent thrombosis: results from a multicenter registry. JACC Cardiovasc Interv. 2014;7:1105–13.CrossRefPubMed
3.
Gur I, Lee W, Akopian G, Rowe VL, Weaver FA, Katz SG. Clinical outcomes and implications of failed infrainguinal endovascular stents. J Vasc Surg. 2011;53:658–66.CrossRefPubMed
4.
5.
6.
Clarke M, Bennett M. The emerging role of vascular smooth muscle cell apoptosis in atherosclerosis and plaque stability. Am J Nephrol. 2006;26:531–5.CrossRefPubMed
7.
Inoue T, Node K. Molecular basis of restenosis and novel issues of drug-eluting stents. Circ J. 2009;73:615–21.CrossRefPubMed
8.
9.
Rizzo P: The Notch pathway: A new therapeutic target in atherosclerosis?; in Ferrari R, (ed): 2015, p A74-A76.
10.
11.
Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L. Rational targeting of Notch signaling in cancer. Oncogene. 2008;27:5124–31.CrossRefPubMed
12.
Li K, Li Y, Wu W, Gordon WR, Chang DW, Lu M, Scoggin S, Fu T, Vien L, Histen G, Zheng J, Martin-Hollister R, Duensing T, Singh S, Blacklow SC, Yao Z, Aster JC, Zhou BB. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem. 2008;283:8046–54.CrossRefPubMed
13.
Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell. 2009;137:1124–35.CrossRefPubMed
14.
Elyaman W, Bradshaw EM, Wang Y, Oukka M, Kivisakk P, Chiba S, Yagita H, Khoury SJ. JAGGED1 and delta1 differentially regulate the outcome of experimental autoimmune encephalomyelitis. J Immunol. 2007;179:5990–8.CrossRefPubMed
15.
Rutz S, Mordmuller B, Sakano S, Scheffold A. Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells. Eur J Immunol. 2005;35:2443–51.CrossRefPubMed
16.
Sekine C, Koyanagi A, Koyama N, Hozumi K, Chiba S, Yagita H. Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes. Arthritis Res Ther. 2012;14:R45.CrossRefPubMedPubMedCentral
17.
van de Walle I, Waegemans E, De MJ, De SG, De SM, Snauwaert S, Vandekerckhove B, Kerre T, Leclercq G, Plum J, Gridley T, Wang T, Koch U, Radtke F, Taghon T. Specific Notch receptor-ligand interactions control human TCR-alphabeta/gammadelta development by inducing differential Notch signal strength. J Exp Med. 2013;210:683–97.CrossRefPubMedPubMedCentral
18.
Boucher JM, Peterson SM, Urs S, Zhang C, Liaw L. The miR-143/145 cluster is a novel transcriptional target of Jagged-1/Notch signaling in vascular smooth muscle cells. J Biol Chem. 2011;286:28312–21.CrossRefPubMedPubMedCentral
19.
Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 2004;18:2730–5.CrossRefPubMedPubMedCentral
20.
Liu H, Kennard S, Lilly B. NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res. 2009;104:466–75.CrossRefPubMedPubMedCentral
21.
Tang Y, Urs S, Liaw L. Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site. Circ Res. 2008;102:661–8.CrossRefPubMedPubMedCentral
22.
Sweeney C, Morrow D, Birney YA, Coyle S, Hennessy C, Scheller A, Cummins PM, Walls D, Redmond EM, Cahill PA. Notch 1 and 3 receptor signaling modulates vascular smooth muscle cell growth, apoptosis, and migration via a CBF-1/RBP-Jk dependent pathway. FASEB J. 2004;18:1421–3.PubMed
23.
Keuylian Z, de Baaij JH, Gueguen M, Glorian M, Rouxel C, Merlet E, Lipskaia L, Blaise R, Mateo V, Limon I. The Notch pathway attenuates interleukin 1beta (IL1beta)-mediated induction of adenylyl cyclase 8 (AC8) expression during vascular smooth muscle cell (VSMC) trans-differentiation. J Biol Chem. 2012;287:24978–89.CrossRefPubMedPubMedCentral
24.
Clement N, Gueguen M, Glorian M, Blaise R, Andreani M, Brou C, Bausero P, Limon I. Notch3 and IL-1beta exert opposing effects on a vascular smooth muscle cell inflammatory pathway in which NF-kappaB drives crosstalk. J Cell Sci. 2007;120:3352–61.CrossRefPubMed
25.
Monsalve E, Perez MA, Rubio A, Ruiz-Hidalgo MJ, Baladron V, Garcia-Ramirez JJ, Gomez JC, Laborda J, Diaz-Guerra MJ. Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. J Immunol. 2006;176:5362–73.CrossRefPubMed
26.
Palaga T, Buranaruk C, Rengpipat S, Fauq AH, Golde TE, Kaufmann SH, Osborne BA. Notch signaling is activated by TLR stimulation and regulates macrophage functions. Eur J Immunol. 2008;38:174–83.CrossRefPubMed
27.
Xu J, Chi F, Guo T, Punj V, Lee WN, French SW, Tsukamoto H. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest. 2015;125:1579–90.CrossRefPubMedPubMedCentral
28.
Fung E, Tang SM, Canner JP, Morishige K, Arboleda-Velasquez JF, Cardoso AA, Carlesso N, Aster JC, Aikawa M. Delta-like 4 induces notch signaling in macrophages: implications for inflammation. Circulation. 2007;115:2948–56.CrossRefPubMed
29.
Nakano T, Fukuda D, Koga JI, Aikawa M. Delta-like ligand 4-Notch signaling in macrophage activation. Arterioscler Thromb Vasc Biol. 2016;36:2038–47.CrossRefPubMed
30.
31.
Zhou J, Li YS, Nguyen P, Wang KC, Weiss A, Kuo YC, Chiu JJ, Shyy JY, Chien S. Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress. Circ Res. 2013;113:40–51.CrossRefPubMedPubMedCentral
32.
Merlet E, Atassi F, Motiani RK, Mougenot N, Jacquet A, Nadaud S, Capiod T, Trebak M, Lompre AM, Marchand A. miR-424/322 regulates vascular smooth muscle cell phenotype and neointimal formation in the rat. Cardiovasc Res. 2013;98:458–68.CrossRefPubMedPubMedCentral
33.
Chen YC, Bui AV, Diesch J, Manasseh R, Hausding C, Rivera J, Haviv I, Agrotis A, Htun NM, Jowett J, Hagemeyer CE, Hannan RD, Bobik A, Peter K. A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling. Circ Res. 2013;113:252–65.CrossRefPubMed
34.
Cao J, Zhang K, Zheng J, Dong R. MicroRNA-146a and -21 cooperate to regulate vascular smooth muscle cell proliferation via modulation of the Notch signaling pathway. Mol Med Rep. 2015;11:2889–95.PubMed
35.
Fan X, Wang E, Wang X, Cong X, Chen X. MicroRNA-21 is a unique signature associated with coronary plaque instability in humans by regulating matrix metalloproteinase-9 via reversion-inducing cysteine-rich protein with Kazal motifs. Exp Mol Pathol. 2014;96:242–9.CrossRefPubMed
36.
Raitoharju E, Lyytikainen LP, Levula M, Oksala N, Mennander A, Tarkka M, Klopp N, Illig T, Kahonen M, Karhunen PJ, Laaksonen R, Lehtimaki T. miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis. 2011;219:211–7.CrossRefPubMed
37.
Nazari-Jahantigh M, Egea V, Schober A, Weber C. MicroRNA-specific regulatory mechanisms in atherosclerosis. J Mol Cell Cardiol. 2014;89:35–41.CrossRefPubMed
38.
Chen T, Huang Z, Wang L, Wang Y, Wu F, Meng S, Wang C. MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages. Cardiovasc Res. 2009;83:131–9.CrossRefPubMed
39.
Huang F, Zhu X, Hu XQ, Fang ZF, Tang L, Lu XL, Zhou SH. Mesenchymal stem cells modified with miR-126 release angiogenic factors and activate Notch ligand Delta-like-4, enhancing ischemic angiogenesis and cell survival. Int J Mol Med. 2013;31:484–92.PubMed
40.
Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J, Megens RT, Heyll K, Noels H, Hristov M, Wang S, Kiessling F, Olson EN, Weber C. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1 3. Nat Med. 2014;20:368–76.CrossRefPubMedPubMedCentral
41.
Wang L, Zhang H, Rodriguez S, Cao L, Parish J, Mumaw C, Zollman A, Kamoka MM, Mu J, Chen DZ, Srour EF, Chitteti BR, HogenEsch H, Tu X, Bellido TM, Boswell HS, Manshouri T, Verstovsek S, Yoder MC, Kapur R, Cardoso AA, Carlesso N. Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-kappaB-dependent manner 2. Cell Stem Cell. 2014;15:51–65.CrossRefPubMedPubMedCentral
42.
Verhoeven BA, Velema E, Schoneveld AH, Vries JP, de Bruin P, Seldenrijk CA, de Kleijn DP, Busser E, van der Graaf YV, Mol F, Pasterkamp G. Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol. 2004;19(12):1127–33.CrossRefPubMed
43.
Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation. 1989;80:1747–56.CrossRefPubMed
44.
Xu S, Fu J, Chen J, Xiao P, Lan T, Le K, Cheng F, He L, Shen X, Huang H, Liu P. Development of an optimized protocol for primary culture of smooth muscle cells from rat thoracic aortas. Cytotechnology. 2009;61:65–72.CrossRefPubMedPubMedCentral
45.
Tilley AE, Harvey BG, Heguy A, Hackett NR, Wang R, O’Connor TP, Crystal RG. Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:457–66.CrossRefPubMed
46.
Alpizar-Alpizar W, Nielsen BS, Sierra R, Illemann M, Ramirez JA, Arias A, Duran S, Skarstein A, Ovrebo K, Lund LR, Laerum OD. Urokinase plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high- and low-risk countries. Int J Cancer. 2010;126:405–15.CrossRefPubMed
47.
Rong JX, Shapiro M, Trogan E, Fisher EA. Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci USA. 2003;100:13531–6.CrossRefPubMedPubMedCentral
48.
Doi H, Iso T, Sato H, Yamazaki M, Matsui H, Tanaka T, Manabe I, Arai M, Nagai R, Kurabayashi M. Jagged1-selective notch signaling induces smooth muscle differentiation via a RBP-Jkappa-dependent pathway. J Biol Chem. 2006;281:28555–64.CrossRefPubMed
49.
Albarran-Juarez J, Kaur H, Grimm M, Offermanns S, Wettschureck N. Lineage tracing of cells involved in atherosclerosis. Atherosclerosis. 2016;251:445–53.CrossRefPubMed
50.
Allahverdian S, Chehroudi AC, McManus BM, Abraham T, Francis GA. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation. 2014;129:1551–9.CrossRefPubMed
51.
Andreeva ER, Pugach IM, Orekhov AN. Subendothelial smooth muscle cells of human aorta express macrophage antigen in situ and in vitro. Atherosclerosis. 1997;135:19–27.CrossRefPubMed
52.
Feil S, Fehrenbacher B, Lukowski R, Essmann F, Schulze-Osthoff K, Schaller M, Feil R. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res. 2014;115:662–7.CrossRefPubMed
53.
Vengrenyuk Y, Nishi H, Long X, Ouimet M, Savji N, Martinez FO, Cassella CP, Moore KJ, Ramsey SA, Miano JM, Fisher EA. Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler Thromb Vasc Biol. 2015;35:535–46.CrossRefPubMedPubMedCentral
54.
Fukuda D, Aikawa E, Swirski FK, Novobrantseva TI, Kotelianski V, Gorgun CZ, Chudnovskiy A, Yamazaki H, Croce K, Weissleder R, Aster JC, Hotamisligil GS, Yagita H, Aikawa M. Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. Proc Natl Acad Sci USA. 2012;109:E1868–77.CrossRefPubMedPubMedCentral
55.
Morrow D, Cullen JP, Cahill PA, Redmond EM. Cyclic strain regulates the Notch/CBF-1 signaling pathway in endothelial cells: role in angiogenic activity. Arterioscler Thromb Vasc Biol. 2007;27:1289–96.CrossRefPubMed
56.
Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, Chandrashekhar YS, Hall JL, Roy S, Zeng Y, Ramakrishnan S. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest. 2010;120:4141–54.CrossRefPubMedPubMedCentral
57.
Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S, Iruela-Arispe L, Simon MC, Keith B. Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood. 2009;114:469–77.CrossRefPubMedPubMedCentral
58.
Riley MF, Bochter MS, Wahi K, Nuovo GJ, Cole SE. Mir-125a-5p-mediated regulation of Lfng is essential for the avian segmentation clock. Dev Cell. 2013;24:554–61.CrossRefPubMedPubMedCentral
59.
Hiratochi M, Nagase H, Kuramochi Y, Koh CS, Ohkawara T, Nakayama K. The Delta intracellular domain mediates TGF-beta/Activin signaling through binding to Smads and has an important bi-directional function in the Notch-Delta signaling pathway. Nucleic Acids Res. 2007;35:912–22.CrossRefPubMedCentral
60.
Edlin RS, Tsai S, Yamanouchi D, Wang C, Liu B, Kent KC. Characterization of primary and restenotic atherosclerotic plaque from the superficial femoral artery: potential role of Smad3 in regulation of SMC proliferation. J Vasc Surg. 2009;49:1289–95.CrossRefPubMedPubMedCentral
61.
Puig O, Yuan J, Stepaniants S, Zieba R, Zycband E, Morris M, Coulter S, Yu X, Menke J, Woods J, Chen F, Ramey DR, He X, O’Neill EA, Hailman E, Johns DG, Hubbard BK, Yee LP, Wright SD, Desouza MM, Plump A, Reiser V. A gene expression signature that classifies human atherosclerotic plaque by relative inflammation status. Circ Cardiovasc Genet. 2011;4:595–604.CrossRefPubMed
62.
Huang J, Hu W, Hu L, Previs RA, Dalton HJ, Yang XY, Sun Y, McGuire M, Rupaimoole R, Nagaraja AS, Kang Y, Liu T, Nick AM, Jennings NB, Coleman RL, Jaffe RB, Sood AK. Dll4 Inhibition plus Aflibercept markedly reduces ovarian tumor growth. Mol Cancer Ther. 2016;15:1344–52.CrossRefPubMed
63.
Stather PW, Sylvius N, Sidloff DA, Dattani N, Verissimo A, Wild JB, Butt HZ, Choke E, Sayers RD, Bown MJ. Identification of microRNAs associated with abdominal aortic aneurysms and peripheral arterial disease. Br J Surg. 2015;102:755–66.CrossRefPubMed
Metadata
Title
Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study
Authors
Giorgio Aquila
Cinzia Fortini
Antonio Pannuti
Serena Delbue
Micaela Pannella
Marco Bruno Morelli
Cristiana Caliceti
Fausto Castriota
Monica de Mattei
Alessia Ongaro
Agnese Pellati
Pasquale Ferrante
Lucio Miele
Luigi Tavazzi
Roberto Ferrari
Paola Rizzo
Alberto Cremonesi
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-017-1199-3

Other articles of this Issue 1/2017

Journal of Translational Medicine 1/2017 Go to the issue

Research

Efficient generation of P53 biallelic knockout Diannan miniature pigs via TALENs and somatic cell nuclear transfer

Research

A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients

Research

Endothelial and smooth muscle cells derived from human cardiac explants demonstrate angiogenic potential and suitable for design of cell-containing vascular grafts

Methodology

Lymph node pooling: a feasible and efficient method of lymph node molecular staging in colorectal carcinoma

Research

Detection of newly produced T and B lymphocytes by digital PCR in blood stored dry on nylon flocked swabs

Research

Gimatecan exerts potent antitumor activity against gastric cancer in vitro and in vivo via AKT and MAPK signaling pathways

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits