title: A potential contribution of dipeptidyl peptidase-4 by the mediation of monocyte differentiation in the development and progression of abdominal aortic aneurysms.
abstract: Abdominal aortic aneurysms (AAAs) are characterized by the destruction of elastin and collagen in the media and adventitia. Dipeptidyl peptidase-4 (DPP-4, an adipokine known as CD26) influences cell signaling, cell-matrix interactions, and the regulation of the functional activity of incretins in metabolic and inflammatory disorders. Although the role of DPP-4 in AAA evolution has been demonstrated, the underlying mechanisms of DPP-4-regulated AAA development remains unknown.
  
  
  
  Patients with AAA (n = 93) and healthy controls (CTL, n = 20) were recruited. Based on computed tomography image analyses, 93 patients were divided into two groups: those with a small AAA (SAA, aortic diameter <5 cm, n = 16) and those with a large AAA (LAA, aortic diameter ≥5 cm, n = 77). Plasma DPP-4, glucagon-like peptide-1 levels, and expression of CD26 on mononuclear cells were analyzed. In addition, phorbol 12-myristate 13-acetate (PMA)-induced THP-1 cells and angiotensin II-infused apolipoprotein EtmlUncmice were used to explore the underlying mechanisms.
  
  
  
  The levels of DPP-4 (μU/μg) increased while active glucagon-like peptide-1 (pM) decreased in patients with AAA in a diameter-dependent manner [CTL: 2.3 ± 1.5 and 3.7 ± 2.4, respectively; SAA: 10.0 ± 10.9 and 2.1 ± 0.9, respectively; LAA: 32.2 ± 15.0 and 1.8 ± 1.1, respectively]. A significant decline in monocyte CD26 expression in patients with AAAs was observed relative to the CTL group. In vitro studies demonstrated that the inhibition of DPP-4 promoted PMA-induced monocytic cells differentiation, with increased CD68 and p21 expression, regulated by extracellular signal-regulated protein kinase 1/2 activation. Furthermore, inhibition of DPP-4 significantly increased the phosphorylation of PYK2 and paxillin in PMA-induced THP-1 cell differentiation. Finally, the animal study was used to confirm the in vitro results that LAA mice showed marked macrophage infiltration in the adventitia with a decreased expression of DPP-4 as compared with SAA mice.
  
  
  
  Increased plasma DPP-4 activity may correlate with aneurysmal development. CD26 on monocytes plays a critical role in cell differentiation, possibly mediated by extracellular signal-regulated protein kinase 1/2-p21 axis signaling pathways and cytoskeletal proteins reassembly. Exploring the role of DPP-4 further may yield potential therapeutic insights.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Hsin-Ying
authors.initials: HY
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Chun-Yao
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Shih
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan; Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan.
authors.forename: Chein-Sung
authors.initials: CS
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: ccshih@vghtpe.gov.tw.
authors.forename: Chun-Che
authors.initials: CC
authors.lastname: Shih
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004108:Dilatation, Pathologic; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D051419:Paxillin / Q000378:metabolism; D034622:RNA Interference; D014162:Transfection
chemical_list: D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; C496061:PXN protein, human; D051419:Paxillin; D052216:Glucagon-Like Peptide 1; D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse