Dipeptidyl peptidase-4 is increased in the abdominal aortic aneurysm vessel wall and is associated with aneurysm disease processes

Autoři: Moritz Lindquist Liljeqvist aff001;  Linnea Eriksson aff001;  Christina Villard aff001;  Mariette Lengquist aff001;  Malin Kronqvist aff001;  Rebecka Hultgren aff001;  Joy Roy aff001
Působiště autorů: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden aff001;  Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227889



Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease, and until today there is no other treatment available than surgical intervention. Dipeptidyl peptidase-4 (DPP4)-inhibitors, used clinically to treat type 2 diabetes, have in murine models been shown to attenuate aneurysm formation and decrease aortic wall matrix degradation, inflammation and apoptosis. Our aim was to investigate if DPP4 is present, active and differentially expressed in human AAA.

Methods and results

DPP4 gene expression was elevated in both media and adventitia of AAA tissue compared with control tissue, as measured by microarrays and qPCR, with consistent findings in external data. The plasma activity of DPP4 was however lower in male patients with AAA compared with age- and gender-matched controls, independently of comorbidity or medication. Immunohistochemical double staining revealed co-localization of DPP4 with cells positive for CD68, CD4 and -8, CD20, and SMA. Gene set enrichment analysis demonstrated that expression of DPP4 in AAA tissue correlated with expression of biological processes related to B- and T-cells, extracellular matrix turnover, peptidase activity, oxidative stress and angiogenesis whereas it correlated negatively with muscle-/actin-related processes.


DPP4 is upregulated in both media and adventitia of human AAA and correlates with aneurysm pathophysiological processes. These results support previous murine mechanistic studies and implicate DPP4 as a target in AAA disease.

Klíčová slova:

Aneurysms – Aorta – Blood plasma – diabetes mellitus – Gene expression – Inflammatory diseases – Macrophages – Microarrays


1. Sakalihasan N, Michel J-B, Katsargyris A, Kuivaniemi H, Defraigne J-O, Nchimi A, et al. Abdominal aortic aneurysms. Nature Reviews Disease Primers. 2018;4: 34. doi: 10.1038/s41572-018-0030-7 30337540

2. Bengtsson H, Bergqvist D. Ruptured abdominal aortic aneurysm: a population-based study. J Vasc Surg. 1993;18: 74–80. doi: 10.1067/mva.1993.42107 8326662

3. Hultgren R, Zommorodi S, Gambe M, Roy J. A Majority of Admitted Patients With Ruptured Abdominal Aortic Aneurysm Undergo and Survive Corrective Treatment: A Population-Based Retrospective Cohort Study. World J Surg. 2016;40: 3080–3087. doi: 10.1007/s00268-016-3705-9 27549597

4. Chaikof EL, Dalman RL, Eskandari MK, Jackson BM, Lee WA, Mansour MA, et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. Journal of Vascular Surgery. 2018;67: 2–77.e2. doi: 10.1016/j.jvs.2017.10.044 29268916

5. Rizas KD, Ippagunta N, Tilson MD. Immune cells and molecular mediators in the pathogenesis of the abdominal aortic aneurysm. Cardiol Rev. 2009;17: 201–210. doi: 10.1097/CRD.0b013e3181b04698 19690470

6. Meier JJ, Nauck MA. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev. 2005;21: 91–117. doi: 10.1002/dmrr.538 15759282

7. De Meester I, Korom S, Van Damme J, Scharpé S. CD26, let it cut or cut it down. Immunol Today. 1999;20: 367–375. doi: 10.1016/s0167-5699(99)01486-3 10431157

8. Zhong J, Rao X, Deiuliis J, Braunstein Z, Narula V, Hazey J, et al. A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. Diabetes. 2013;62: 149–157. doi: 10.2337/db12-0230 22936179

9. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. The Lancet. 2006;368: 1696–1705. doi: 10.1016/S0140-6736(06)69705-5

10. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33: 187–215. doi: 10.1210/er.2011-1052 22323472

11. Sjöholm A. Impact of glucagon-like peptide-1 on endothelial function. Diabetes Obes Metab. 2009;11 Suppl 3: 19–25. doi: 10.1111/j.1463-1326.2009.01074.x 19878258

12. Nyström T. The Potential Beneficial Role of Glucagon-like Peptide-1 in Endothelial Dysfunction and Heart Failure Associated with Insulin Resistance. Horm Metab Res. 2008;40: 593–606. doi: 10.1055/s-0028-1082326 18792870

13. Bao W, Morimoto K, Hasegawa T, Sasaki N, Yamashita T, Hirata K, et al. Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats. J Vasc Surg. 2014;59: 1098–1108. doi: 10.1016/j.jvs.2013.04.048 23790558

14. Lu HY, Huang CY, Shih CM, Chang WH, Tsai CS, Lin FY, et al. Dipeptidyl peptidase-4 inhibitor decreases abdominal aortic aneurysm formation through GLP-1-dependent monocytic activity in mice. PLoS ONE. 2015;10: e0121077. doi: 10.1371/journal.pone.0121077 25876091

15. Kohashi K, Hiromura M, Mori Y, Terasaki M, Watanabe T, Kushima H, et al. A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice. J Atheroscler Thromb. 2016;23: 441–454. doi: 10.5551/jat.31997 26549734

16. Lu H-Y, Huang C-Y, Shih C-M, Lin Y-W, Tsai C-S, Lin F-Y, et al. A potential contribution of dipeptidyl peptidase-4 by the mediation of monocyte differentiation in the development and progression of abdominal aortic aneurysms. J Vasc Surg. 2017;66: 1217–1226.e1. doi: 10.1016/j.jvs.2016.05.093 27887857

17. Takahara Y, Tokunou T, Ichiki T. Suppression of Abdominal Aortic Aneurysm Formation in Mice by Teneligliptin, a Dipeptidyl Peptidase-4 Inhibitor. J Atheroscler Thromb. 2018;25: 698–708. doi: 10.5551/jat.42481 29321388

18. Raffort J, Chinetti G, Lareyre F. Glucagon-Like peptide-1: A new therapeutic target to treat abdominal aortic aneurysm? Biochimie. 2018;152: 149–154. doi: 10.1016/j.biochi.2018.06.026 30103898

19. Hans SS, Jareunpoon O, Balasubramaniam M, Zelenock GB. Size and location of thrombus in intact and ruptured abdominal aortic aneurysms. J Vasc Surg. 2005;41: 584–588. doi: 10.1016/j.jvs.2005.01.004 15874920

20. Perisic L, Hedin E, Razuvaev A, Lengquist M, Osterholm C, Folkersen L, et al. Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis. Arterioscler Thromb Vasc Biol. 2013;33: 2432–2443. doi: 10.1161/ATVBAHA.113.301743 23908247

21. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43: e47. doi: 10.1093/nar/gkv007 25605792

22. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2019. https://www.R-project.org/

23. RStudio Team. RStudio: Integrated Development for R. RStudio, Inc., Boston, MA; http://www.rstudio.com/.

24. Wickham H. ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York; 2009. http://ggplot2.org

25. Wickham H. tidyverse: Easily Install and Load the “Tidyverse.” 2017. https://CRAN.R-project.org/package=tidyverse

26. Lenk GM, Tromp G, Weinsheimer S, Gatalica Z, Berguer R, Kuivaniemi H. Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms. BMC Genomics. 2007;8: 237. doi: 10.1186/1471-2164-8-237 17634102

27. Biros E, Gäbel G, Moran CS, Schreurs C, Lindeman JHN, Walker PJ, et al. Differential gene expression in human abdominal aortic aneurysm and aortic occlusive disease. Oncotarget. 2015;6: 12984–12996. doi: 10.18632/oncotarget.3848 25944698

28. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. PNAS. 2005;102: 15545–15550. doi: 10.1073/pnas.0506580102 16199517

29. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25: 25–29. doi: 10.1038/75556 10802651

30. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Res. 2003;13: 2498–2504. doi: 10.1101/gr.1239303 14597658

31. Consortium GTEx. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45: 580–585. doi: 10.1038/ng.2653 23715323

32. Eagleton MJ. Inflammation in abdominal aortic aneurysms: cellular infiltrate and cytokine profiles. Vascular. 2012;20: 278–283. doi: 10.1258/vasc.2011.201207 23091264

33. Wronkowitz N, Görgens SW, Romacho T, Villalobos LA, Sánchez-Ferrer CF, Peiró C, et al. Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. Biochim Biophys Acta. 2014;1842: 1613–1621. doi: 10.1016/j.bbadis.2014.06.004 24928308

34. Röhrborn D, Eckel J, Sell H. Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Lett. 2014;588: 3870–3877. doi: 10.1016/j.febslet.2014.08.029 25217834

35. Choke E, Cockerill GW, Dawson J, Chung Y-L, Griffiths J, Wilson RW, et al. Hypoxia at the site of abdominal aortic aneurysm rupture is not associated with increased lactate. Ann N Y Acad Sci. 2006;1085: 306–310. doi: 10.1196/annals.1383.005 17182947

36. Vorp DA, Lee PC, Wang DH, Makaroun MS, Nemoto EM, Ogawa S, et al. Association of intraluminal thrombus in abdominal aortic aneurysm with local hypoxia and wall weakening. J Vasc Surg. 2001;34: 291–299. doi: 10.1067/mva.2001.114813 11496282

37. Ervinna N, Mita T, Yasunari E, Azuma K, Tanaka R, Fujimura S, et al. Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology. 2013;154: 1260–1270. doi: 10.1210/en.2012-1855 23337530

38. Akita K, Isoda K, Shimada K, Daida H. Dipeptidyl-peptidase-4 inhibitor, alogliptin, attenuates arterial inflammation and neointimal formation after injury in low-density lipoprotein (LDL) receptor-deficient mice. J Am Heart Assoc. 2015;4: e001469. doi: 10.1161/JAHA.114.001469 25770025

39. Eriksson L, Röhl S, Saxelin R, Lengquist M, Kronqvist M, Caidahl K, et al. Effects of Linagliptin on Vessel Wall Healing in the Rat Model of Arterial Injury Under Normal and Diabetic Conditions. J Cardiovasc Pharmacol. 2017;69: 101–109 27875385

40. Krizhanovskii C, Ntika S, Olsson C, Eriksson P, Franco-Cereceda A. Elevated circulating fasting glucagon-like peptide-1 in surgical patients with aortic valve disease and diabetes. Diabetol Metab Syndr. 2017;9: 79. doi: 10.1186/s13098-017-0279-0 29046727

41. Brown LC, Powell JT. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. UK Small Aneurysm Trial Participants. Ann Surg. 1999;230: 289–296; discussion 296–297. doi: 10.1097/00000658-199909000-00002 10493476

42. Siika A, Lindquist Liljeqvist M, Zommorodi S, Nilsson O, Andersson P, Gasser TC, et al. A large proportion of patients with small ruptured abdominal aortic aneurysms are women and have chronic obstructive pulmonary disease. PLoS ONE. 2019;14: e0216558. doi: 10.1371/journal.pone.0216558 31136570

43. Kuivaniemi H, Ryer EJ, Elmore JR, Tromp G. Understanding the pathogenesis of abdominal aortic aneurysms. Expert Review of Cardiovascular Therapy. 2015;13: 975–987. doi: 10.1586/14779072.2015.1074861 26308600

44. Choke E, Thompson MM, Dawson J, Wilson WRW, Sayed S, Loftus IM, et al. Abdominal Aortic Aneurysm Rupture Is Associated With Increased Medial Neovascularization and Overexpression of Proangiogenic Cytokines. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26: 2077–2082. doi: 10.1161/01.ATV.0000234944.22509.f9 16809548

45. Lareyre F, Clément M, Raffort J, Pohlod S, Patel M, Esposito B, et al. TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm. Arterioscler Thromb Vasc Biol. 2017;37: 2171–2181. doi: 10.1161/ATVBAHA.117.309999 28912363

46. Lu G, Su G, Davis JP, Schaheen B, Downs E, Roy RJ, et al. A novel chronic advanced stage abdominal aortic aneurysm murine model. J Vasc Surg. 2017;66: 232–242.e4. doi: 10.1016/j.jvs.2016.07.105 28274752

47. Löster K, Zeilinger K, Schuppan D, Reutter W. The cysteine-rich region of dipeptidyl peptidase IV (CD 26) is the collagen-binding site. Biochem Biophys Res Commun. 1995;217: 341–348. doi: 10.1006/bbrc.1995.2782 8526932

48. Cheng H-C, Abdel-Ghany M, Pauli BU. A novel consensus motif in fibronectin mediates dipeptidyl peptidase IV adhesion and metastasis. J Biol Chem. 2003;278: 24600–24607. doi: 10.1074/jbc.M303424200 12716896

49. Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S, Chen W-T. The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res. 2006;66: 4652–4661. doi: 10.1158/0008-5472.CAN-05-1245 16651416

50. Röhrborn D, Wronkowitz N, Eckel J. DPP4 in Diabetes. Front Immunol. 2015;6: 386. doi: 10.3389/fimmu.2015.00386 26284071

51. Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci. 2005;108: 277–292. doi: 10.1042/CS20040302 15584901

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden