Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart
- 588 Downloads
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.
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.
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.
KeywordsAngiotensin II receptors ACE2 Collagen Cardiac fibrosis Dipeptidyl peptidase-4 Glucagon-like peptide-1
This study was supported in part by grants from the Mercer University School of Medicine, the Medcen Community Health Foundation, Georgia, the National Natural Science Foundation of China (81170145) and the Health Department Planning Commission of Shanxi (201201041).
Conflict of interest
No conflicts of interest are declared by the authors.
- 14.Knudsen LB. Liraglutide: the therapeutic promise from animal models. Int J Clin Pract. 2010;64:4–11.Google Scholar
- 15.Kern M, Kioting N, Niessen HG, Thomas L, Stiller D, Mark M, et al. Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. PLoS One. 2012;7:e38744.Google Scholar
- 16.Wang NP, Wang ZF, Tootle S, Philip TJ, Zhao ZQ. Curcumin promotes cardiac repair and ameliorates cardiac dysfunction following myocardial infarction. Br J Pharmacol. 2012;167:1550–62.Google Scholar
- 17.Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang K, et al. Hydrolysis of biological peptide by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002;277:14838–43.Google Scholar
- 38.Patel VB, Bodiga S, Fan D, Das SK, Wang ZH, Wang W, et al. Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2 - null mice. Hypertension. 2012;59:1195–203.PubMedCrossRefGoogle Scholar
- 42.Hanafy H, Tavasoli M, Jamali F. Inflammation alters angiotensin converting enzymes (ACE and ACE-2) balance in rat heart. Inflammation. 2011;34:609–13.Google Scholar