title: Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro.
abstract: OBJECTIVE
  Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can not only lower blood glucose levels, but also alleviate cardiac remodeling after myocardial ischemia and hypertension. In the present study, we investigated the effects of a DPP-4 inhibitor (linagliptin) and a GLP-1 activator (liraglutide) on glucose- and angiotensin II (Ang II)-induced collagen formation and cytoskeleton reorganization in cardiac fibroblasts in vitro, and elucidated the related mechanisms.
  
  
  METHODS
  Cardiac fibroblasts were isolated from the hearts of 6-week-old C57BL/6 mice, and then exposed to different concentrations of glucose or Ang II for 24 h. The expression of fibrotic signals (fibronectin, collagen-1, -3 and -4), as well as ERK1/2 and NF-κB-p65 in the fibroblasts was examined using Western blotting assays. F-actin degradation was detected under inverted laser confocal microscope in fibroblasts stained with Rhodamine phalloidin.
  
  
  RESULTS
  Glucose (1-40 mmol/L) and Ang II (10-8-10-5mol/L) dose-dependently increased the expression of fibronectin, collagens, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. High concentrations of glucose (≥40 mmol/L) and Ang II (≥10-6mol/L) caused a significant degradation of F-actin (less assembly F-actin fibers and more disassembly fibers). ERK1/2 inhibitor U0126 (10 μmol/L) and NF-κB inhibitor JSH-23 (10 μmol/L) both markedly suppressed glucose- and angiotensin II-induced fibronectin and collagen expressions in cardiac fibroblasts. Furthermore, pretreatment with liraglutide (10-100 nmol/L) or linagliptin (3 and 30 nmol/L) significantly decreased glucose- and Ang II-induced expression of fibrotic signals, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. Moreover, pretreatment with liraglutide (30 nmol/L) or liraglutide (100 nmol/L) markedly inhibited glucose-induced F-actin degradation, however, only liraglutide inhibited Ang II-induced F-actin degradation.
  
  
  CONCLUSIONS
  Linagliptin and liraglutide inhibit glucose- and Ang II-induced collagen formation in cardiac fibroblasts via activation of the ERK/NF-κB/pathway. Linagliptin and liraglutide also markedly inhibit glucose-induced F-actin degradation in cardiac fibroblasts, but only liraglutide inhibits Ang II-induced F-actin degradation.
authors: Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang 453003, China.|Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Xian-Wei
authors: XW
authors: Wang
authors: College of Life Science, Henan Normal University, Xinxiang 453007, China.
authors: Fen-Xi
authors: FX
authors: Zhang
authors: Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang 453003, China.
authors: Fen
authors: F
authors: Yang
authors: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Zu-Feng
authors: ZF
authors: Ding
authors: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Nidhi
authors: N
authors: Agarwal
authors: Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang 453003, China.
authors: Zhi-Kun
authors: ZK
authors: Guo
authors: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Jawahar L
authors: JL
authors: Mehta
mesh_terms: D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D003094:Collagen / Q000096:biosynthesis*; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D005947:Glucose / Q000494:pharmacology; D000069476:Linagliptin / Q000494:pharmacology*; D000069450:Liraglutide / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*
chemical_list: D000199:Actins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000804:Angiotensin II; D000069476:Linagliptin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D003094:Collagen; D005947:Glucose