Cardiovascular Drugs and Therapy

, Volume 29, Issue 3, pp 243–255 | Cite as

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

  • Li-Hui Zhang
  • Xue-Fen Pang
  • Feng Bai
  • Ning-Ping Wang
  • Ahmed Ijaz Shah
  • Robert J. McKallip
  • Xue-Wen Li
  • Xiong Wang
  • Zhi-Qing Zhao



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.


Angiotensin 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.


  1. 1.
    Liehn EA, Postea O, Curaj A, Marx N. Repair after myocardial infarction between fantasy and reality. J Am Coll Cardiol. 2011;58:2357–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Weber KT. Fibrosis in hypertension heart disease: focus on cardiac fibroblasts. J Hypertens. 2004;22:47–60.PubMedCrossRefGoogle Scholar
  3. 3.
    Crowley MJ, Powers BJ, Myers ER, McBroom AJ, Sanders G. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers for treatment of ischemic heart disease: future research needs prioritization. Am Heart J. 2012;163:777–82.PubMedCrossRefGoogle Scholar
  4. 4.
    Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther. 2008;120:292–316.PubMedCrossRefGoogle Scholar
  5. 5.
    Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T. AT2 receptor and tissue injury: therapeutic implications. Curr Hypertens Res. 2014;16:416–26.CrossRefGoogle Scholar
  6. 6.
    Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010;2:247–57.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Ram CVS. Angiotensin receptor blockers: current status and future prospects. Am J Med. 2008;121:656–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Anavekar NS, Solomon SD. Angiotensin II receptor blockade and ventricular remodeling. JRAAS. 2005;6:43–8.PubMedGoogle Scholar
  9. 9.
    Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation. 2004;109:2492–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Pabreja K, Mohd MA, Kode C, Wootten D, Furness SGB. Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation. Br J Pharmacol. 2014;171:1114–28.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Hausenloy DJ, Whitington HJ, Wynne AM, Begum SS, Theodorou L, Riksen N, et al. Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner. Cardiovasc Diabetol. 2013;22:154.CrossRefGoogle Scholar
  12. 12.
    Johansen OE, Neubache D, Eynatten MV, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified prospective, and adjudicated mata-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3–13.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Wang XM, Yang YJ, Wu YJ. The emerging role of dipeptidyl peptidase-4 inhibitors in cardiovascular protection: current position and perspectives. Cardiovasc Drugs Ther. 2013;27:297–307.PubMedCrossRefGoogle Scholar
  14. 14.
    Knudsen LB. Liraglutide: the therapeutic promise from animal models. Int J Clin Pract. 2010;64:4–11.Google Scholar
  15. 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. 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. 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
  18. 18.
    Clarke SJ, McCormick LM, Dutka DP. Optimizing cardioprotection during myocardial ischemia: targeting potential intracellular pathways with glucagon-like peptide-1. Cardiovasc Diabetol. 2014;13:12–22.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Dai Y, Mehta JL, Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 endothelial cell by repressing nuclear factor-kappa B activation. Cardiovasc Drugs Ther. 2013;27:371–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, et al. GLP-1 receptor agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:975–83.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Bose AK, Mocanu MM, Carr RD, Yellon DM. Myocardial ischemia-reperfusion injury is attenuated by intact glucagon like peptide-1 (GLP-1) in the in vitro rat heart and may involve the p70s6K pathway. Cardiovasc Drugs Ther. 2007;21:253–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Ravassa S, Zudaire A, Diez J. GLP-1 and cardioprotection: from bench to bedside. Cardiovasc Res. 2012;94:316–23.PubMedCrossRefGoogle Scholar
  23. 23.
    Jones ES, Black MJ, Widdop RE. Angiotensin AT2 receptor contributes to cardiovascular remodeling of aged rats during chronic AT1 receptor blockade. J Mol Cell Cardiol. 2004;37:1023–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Yuan SM, Jing H. Cardiac pathologies in relation to Smad-dependent pathways. Interact Cardiovasc Thorac Surg. 2010;11:455–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Euler-Taimor G, Heger J. The complex pattern of SMAD signaling in the cardiovascular system. Cardiovasc Res. 2006;69:15–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Bujak M, Frangogiannis NG. The role of TGF-β signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007;74:184–95.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Wang B, Omara A, Angelovska T, Drobic V, Rattan SG, Jones SC, et al. Regulation of collagen synthesis by inhibitory Smad7 in cardiac myofibroblasts. Am J Physiol Heart Circ Physiol. 2007;293:H1282–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Hao JM, Wang BQ, Jones SC, Jassal DS, Dixon IMC. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol Heart Circ Physiol. 2000;279:H3020–30.PubMedGoogle Scholar
  29. 29.
    Iwasaki T, Mukasa K, Yoneda M, Ito S, Yamada Y, Mori Y, et al. A marked attenuation of production of collagen type I from cardiac fibroblasts by dehydroepiandrosterone. Am J Physiol Endocrinol Metab. 2005;288:E1222–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Gao XR, He XY, Luo B, Peng LY, Lin J, Zuo ZY. Angiotensin II increases collagen I expression via transforming growth factor-beta1 and extracellular signal-regulated kinase in cardiac fibroblasts. Eur J Pharmacol. 2009;606:115–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Qi GM, Jia L, Li YL, Bian Y, Cheng JZ, Li HH, et al. Angiotensin II infusion-induced inflammation, monocytic fibroblast precursor infiltration and cardiac fibrosis are pressure dependent. Cardiovasc Toxicol. 2011;11:157–67.PubMedCrossRefGoogle Scholar
  32. 32.
    Hocher B, Sharkovska Y, Mark M, Klein T, Pfab T. The novel DPP-4 inhibitor linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats. Int J Cardiol. 2013;167:87–93.PubMedCrossRefGoogle Scholar
  33. 33.
    Dai Y, Dai D, Wang XW, Ding ZF, Mehta JL. DPP-4 inhibitors repress NLRP3 inflammasome and interleukin-1beta via GLP-1 receptor in macrophages through protein kinase C pathway. Cardiovasc Drugs Ther. 2014;28:425–32.PubMedCrossRefGoogle Scholar
  34. 34.
    Sortino MA, Sinagra T, Canonico PL. Linagliptin: a thorough characterization beyond its clinical efficacy. Front Endocrinol. 2013;4:1–9.CrossRefGoogle Scholar
  35. 35.
    Keidar S, Kaplan M, Gamliel -Lazarovich A. ACE2 of the heart: from angiotensin I to angiotensin (1-7). Cardiovasc Res. 2007;73:463–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, et al. Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension. 2006;47:718–26.PubMedCrossRefGoogle Scholar
  37. 37.
    Benter IF, Yousif MHM, Cojocel C, AI-Maghrebi M, Diz DI. Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol. 2007;292:H666–72.PubMedCrossRefGoogle Scholar
  38. 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
  39. 39.
    Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM, et al. Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7). Am J Physiol Heart Circ Physiol. 2007;292:H736–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Pyke C, Heller S, Kirk RK, Orskov C, Reedtz-Runge S, Kaastrup P, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155:1280–90.PubMedCrossRefGoogle Scholar
  41. 41.
    Nikolaidis LA, Elahi D, Shen YT, Shannon RP. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005;289:H2401–8.PubMedCrossRefGoogle Scholar
  42. 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
  43. 43.
    Klein T, Fuji M, Sandel J, Shibazaki Y, Wakamatsu K, Mark M, et al. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis. Med Mol Morphol. 2014;47:137–49.PubMedCrossRefGoogle Scholar
  44. 44.
    Liu Q, Anderson C, Broyde A, Polizzi C, Fernandez R, Baron A, et al. Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure. Cardiovasc Diabetol. 2010;9:76–90.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Li-Hui Zhang
    • 1
  • Xue-Fen Pang
    • 2
  • Feng Bai
    • 1
  • Ning-Ping Wang
    • 5
  • Ahmed Ijaz Shah
    • 3
  • Robert J. McKallip
    • 4
  • Xue-Wen Li
    • 1
  • Xiong Wang
    • 1
  • Zhi-Qing Zhao
    • 2
    • 5
  1. 1.Department of CardiologyShanxi Medical University, Shanxi Dayi HospitalTaiyuanChina
  2. 2.Department of PhysiologyShanxi Medical UniversityTaiyuanChina
  3. 3.Department of Internal MedicineMercer University School of MedicineMaconUSA
  4. 4.Division of Basic Biomedical SciencesMercer University School of MedicineMaconUSA
  5. 5.Cardiovascular Research LaboratoryMercer University School of MedicineSavannahUSA

Personalised recommendations