TY - JOUR
T1 - A potential contribution of dipeptidyl peptidase-4 by the mediation of monocyte differentiation in the development and progression of abdominal aortic aneurysms
AU - Lu, Hsin Ying
AU - Huang, Chun-Yao
AU - Shih, Chun-Ming
AU - Lin, Yi Wen
AU - Tsai, Chein Sung
AU - Lin, Feng-Yen
AU - Shih, Chun Che
N1 - Publisher Copyright:
© 2016 Society for Vascular Surgery
PY - 2017/10
Y1 - 2017/10
N2 - Objective: 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. This is an important issue to explore. Methods: 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). According to the critical roles of monocytic cells in AAA formation, 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 EtmlUnc mice were used to explore the underlying mechanisms. Results: The levels of DPP-4 (μU/μg) increased, and 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 CD26 expression of monocytes in patients with AAAs was observed relative to the CTL group. In vitro study demonstrated that the inhibition of DPP-4 markedly promoted PMA-induced monocytic cells differentiation by increased CD68 and p21 expression, which 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 compared with SAA mice. Conclusions: We support that the increase of plasma DPP-4 activity may correlate with aneurysmal development. CD26 on monocytes plays a critical role in cell differentiation, which may mediate by extracellular signal-regulated protein kinase 1/2-p21 axis signaling pathways and cytoskeletal proteins reassembly. The AAA influent factor, DPP-4, may involve future therapeutic element.
AB - Objective: 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. This is an important issue to explore. Methods: 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). According to the critical roles of monocytic cells in AAA formation, 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 EtmlUnc mice were used to explore the underlying mechanisms. Results: The levels of DPP-4 (μU/μg) increased, and 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 CD26 expression of monocytes in patients with AAAs was observed relative to the CTL group. In vitro study demonstrated that the inhibition of DPP-4 markedly promoted PMA-induced monocytic cells differentiation by increased CD68 and p21 expression, which 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 compared with SAA mice. Conclusions: We support that the increase of plasma DPP-4 activity may correlate with aneurysmal development. CD26 on monocytes plays a critical role in cell differentiation, which may mediate by extracellular signal-regulated protein kinase 1/2-p21 axis signaling pathways and cytoskeletal proteins reassembly. The AAA influent factor, DPP-4, may involve future therapeutic element.
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U2 - 10.1016/j.jvs.2016.05.093
DO - 10.1016/j.jvs.2016.05.093
M3 - Article
C2 - 27887857
AN - SCOPUS:85007022977
SN - 0741-5214
VL - 66
SP - 1217
EP - 1226
JO - Journal of Vascular Surgery
JF - Journal of Vascular Surgery
IS - 4
ER -