title: Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT 2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart.
abstract: OBJECTIVE
  The glucagon-like peptide-1 (GLP-1) has been shown to exert cardioprotective effects in animals and patients. This study tests the hypothesis that preservation of GLP-1 by the GLP-1 receptor agonist liraglutide or the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is associated with a reduction of angiotensin (Ang) II-induced cardiac fibrosis.
  
  
  RESULTS
  Sprague-Dawley rats were subjected to Ang II (500 ng/kg/min) infusion using osmotic minipumps for 4 weeks. Liraglutide (0.3 mg/kg) was subcutaneously injected twice daily or linagliptin (8 mg/kg) was administered via oral gavage daily during Ang II infusion. Relative to the control, liraglutide, but not linagliptin decreased MAP (124 ± 4 vs. 200 ± 7 mmHg in control, p < 0.003). Liraglutide and linagliptin comparatively reduced the protein level of the Ang II AT1 receptor and up-regulated the AT2 receptor as identified by a reduced AT1/AT2 ratio (0.4 ± 0.02 and 0.7 ± 0.01 vs. 1.4 ± 0.2 in control, p < 0.05), coincident with the less locally-expressed AT1 receptor and enhanced AT2 receptor in the myocardium and peri-coronary vessels. Both drugs significantly reduced the populations of macrophages (16 ± 6 and 19 ± 7 vs. 61 ± 29 number/HPF in control, p < 0.05) and α-SMA expressing myofibroblasts (17 ± 7 and 13 ± 4 vs. 66 ± 29 number/HPF in control, p < 0.05), consistent with the reduction in expression of TGFβ1 and phospho-Smad2/3, and up-regulation of Smad7. Furthermore, ACE2 activity (334 ± 43 and 417 ± 51 vs. 288 ± 19 RFU/min/μg protein in control, p < 0.05) and GLP-1 receptor expression were significantly up-regulated. Along with these modulations, the synthesis of collagen I and tissue fibrosis were inhibited as determined by the smaller collagen-rich area and more viable myocardium.
  
  
  CONCLUSIONS
  These results demonstrate for the first time that preservation of GLP-1 using liraglutide or linagliptin is effective in inhibiting Ang II-induced cardiac fibrosis, suggesting that these drugs could be selected as an adjunctive therapy to improve clinical outcomes in the fibrosis-derived heart failure patients with or without diabetes.
authors.affiliation: Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Zhang
authors.forename: Xue-Fen
authors.initials: XF
authors.lastname: Pang
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.forename: Ning-Ping
authors.initials: NP
authors.lastname: Wang
authors.forename: Ahmed Ijaz
authors.initials: AI
authors.lastname: Shah
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McKallip
authors.forename: Xue-Wen
authors.initials: XW
authors.lastname: Li
authors.forename: Xiong
authors.initials: X
authors.lastname: Wang
authors.forename: Zhi-Qing
authors.initials: ZQ
authors.lastname: Zhao
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000069476:Linagliptin / Q000494:pharmacology / Q000627:therapeutic use; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis* / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis* / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D000069476:Linagliptin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2