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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.
- Source :
-
Cardiovascular drugs and therapy [Cardiovasc Drugs Ther] 2015 Jun; Vol. 29 (3), pp. 243-55. - Publication Year :
- 2015
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Abstract
- Purpose: 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.<br />Methods and 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.<br />Conclusion: 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.
- Subjects :
- Angiotensin-Converting Enzyme 2
Animals
Blood Pressure drug effects
Collagen metabolism
Fibrosis chemically induced
Fibrosis drug therapy
Fibrosis metabolism
Linagliptin pharmacology
Linagliptin therapeutic use
Liraglutide pharmacology
Liraglutide therapeutic use
Male
Myocardium enzymology
Myocardium pathology
Rats
Receptor, Angiotensin, Type 1 metabolism
Receptor, Angiotensin, Type 2 metabolism
Smad Proteins metabolism
Transforming Growth Factor beta1 biosynthesis
Angiotensin II adverse effects
Fibrosis pathology
Gene Expression drug effects
Glucagon-Like Peptide 1 metabolism
Myocardium metabolism
Peptidyl-Dipeptidase A metabolism
Receptor, Angiotensin, Type 1 biosynthesis
Receptor, Angiotensin, Type 2 biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1573-7241
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cardiovascular drugs and therapy
- Publication Type :
- Academic Journal
- Accession number :
- 25994830
- Full Text :
- https://doi.org/10.1007/s10557-015-6592-7