Molecular Medicine

, Volume 21, Issue 1, pp 15–25 | Cite as

Glucagon-Like Peptide 1 Protects against Hyperglycemic-Induced Endothelial-to-Mesenchymal Transition and Improves Myocardial Dysfunction by Suppressing Poly(ADP-Ribose) Polymerase 1 Activity

  • Fei Yan
  • Guang-hao Zhang
  • Min Feng
  • Wei Zhang
  • Jia-ning Zhang
  • Wen-qian Dong
  • Cheng Zhang
  • Yun Zhang
  • Li Chen
  • Ming-Xiang Zhang
Research Article


Under high glucose conditions, endothelial cells respond by acquiring fibroblast characteristics, that is, endothelial-to-mesenchymal transition (EndMT), contributing to diabetic cardiac fibrosis. Glucagon-like peptide-1 (GLP-1) has cardioprotective properties independent of its glucose-lowering effect. However, the potential mechanism has not been fully clarified. Here we investigated whether GLP-1 inhibits myocardial EndMT in diabetic mice and whether this is mediated by suppressing poly(ADP-ribose) polymerase 1 (PARP-1). Streptozotocin diabetic C57BL/6 mice were treated with or without GLP-1 analog (24 nmol/kg daily) for 24 wks. Transthoracic echocardiography was performed to assess cardiac function. Human aortic endothelial cells (HAECs) were cultured in normal glucose (NG) (5.5 mmol/L) or high glucose (HG) (30 mmol/L) medium with or without GLP-1analog. Immunofluorescent staining and Western blot were performed to evaluate EndMT and PARP-1 activity. Diabetes mellitus attenuated cardiac function and increased cardiac fibrosis. Treatment with the GLP-1 analog improved diabetes mellitus-related cardiac dysfunction and cardiac fibrosis. Immunofluorescence staining revealed that hyperglycemia markedly increased the percentage of von Willebrand factor (vWF)+/alpha smooth muscle actin (α-SMA)+ cells in total α-SMA+ cells in diabetic hearts compared with controls, which was attenuated by GLP-1 analog treatment. In cultured HAECs, immunofluorescent staining and Western blot also showed that both GLP-1 analog and PARP-1 gene silencing could inhibit the HG-induced EndMT. In addition, GLP-1 analog could attenuate PARP-1 activation by decreasing the level of reactive oxygen species (ROS). Therefore, GLP-1 treatment could protect against the hyperglycemia-induced EndMT and myocardial dysfunction. This effect is mediated, at least partially, by suppressing PARP-1 activation.



This work was supported by the National 973 Basic Research program of China (no. 2015CB553604), the National Natural Science Foundation of China (81170275),81370412, and 91439201) and the State Program of National Natural Science Foundation of China for Innovative Research Group (81321061).


  1. 1.
    Rosenbloom J, Castro SV, Jimenez SA. (2010) Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann. Intern. Med. 152:159–66.CrossRefGoogle Scholar
  2. 2.
    Wei J, Bhattacharyya S, Tourtellotte WG, Varga J. (2011) Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy. Autoimmunity Reviews. 10:267–75.CrossRefGoogle Scholar
  3. 3.
    Wynn TA. (2008) Cellular and molecular mechanisms of fibrosis. J. Pathol. 214:199–210.CrossRefGoogle Scholar
  4. 4.
    Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67:10123–8.CrossRefGoogle Scholar
  5. 5.
    Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R. (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19:2282–7.CrossRefGoogle Scholar
  6. 6.
    Zeisberg EM, et al. (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13:952–61.CrossRefGoogle Scholar
  7. 7.
    Widyantoro B, et al. (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation. 121:2407–18.CrossRefGoogle Scholar
  8. 8.
    Li J, et al. (2010) Blockade of endothelial-mesenchymal 25 transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. Diabetes. 59:2612–24.CrossRefGoogle Scholar
  9. 9.
    Tang RN, et al. (2013) Effects of angiotensin II receptor blocker on myocardial endothelial-to-mesenchymal transition in diabetic rats. Int. J. Cardiol. 162:92–9.CrossRefGoogle Scholar
  10. 10.
    Schraufstatter IU, et al. (1986) Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. Proc. Nalt. Acad. Sci. U. S. A. 83:4908–12.CrossRefGoogle Scholar
  11. 11.
    Nguewa PA, Fuertes MA, Alonso C, Perez JM. (2003) Pharmacological modulation of poly(ADP-ribose) polymerase-mediated cell death: exploitation in cancer chemotherapy. Mol. Pharmacol. 64:1007–14.CrossRefGoogle Scholar
  12. 12.
    Szabo C, Zingarelli B, O’Connor M, Salzman AL. (1996) DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc. Nalt. Acad. Sci. U. S. A. 93:1753–8.CrossRefGoogle Scholar
  13. 13.
    Du X, et al. (2003) Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J. Clin. Invest. 112:1049–57.CrossRefGoogle Scholar
  14. 14.
    Chiu J, Xu BY, Chen S, Feng B, Chakrabarti S. (2008) Oxidative stress-induced, poly(ADP-ribose) polymerase-dependent upregulation of ET-1 expression in chronic diabetic complications. Can. J. Physiol Pharmacol. 86:365–72.CrossRefGoogle Scholar
  15. 15.
    Chiarugi A, Moskowitz MA. (2003) Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J. Neurochem. 85:306–17.CrossRefGoogle Scholar
  16. 16.
    Mota RA, et al. (2008) Poly(ADP-ribose) polymerase-1 inhibition increases expression of heat shock proteins and attenuates heat stroke-induced liver injury. Crit. Care Med. 36:526–34.CrossRefGoogle Scholar
  17. 17.
    Rieder F, et al. (2011) Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis. Am. J. Path. 179:2660–73.CrossRefGoogle Scholar
  18. 18.
    Monji A, et al. (2013) Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol. 305:H295–304.CrossRefGoogle Scholar
  19. 19.
    Noyan-Ashraf MH, et al. (2013) A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation. 127:74–85.CrossRefGoogle Scholar
  20. 20.
    Poornima IG, Parikh P, Shannon RP. (2006) Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ. Res. 98:596–605.CrossRefGoogle Scholar
  21. 21.
    Battiprolu PK, Gillette TG, Wang ZV, Lavandero S, Hill JA. (2010) Diabetic cardiomyopathy: mechanisms and therapeutic targets. Drug Discov. Today. 7:e135–43.CrossRefGoogle Scholar
  22. 22.
    Liu FQ, et al. (2011) Glucagon-like peptide 1 protects microvascular endothelial cells by inactivating the PARP-1/iNOS/NO pathway. Mol. Cell. Endocrinol. 339:25–33.CrossRefGoogle Scholar
  23. 23.
    Shevalye H, Maksimchyk Y, Watcho P, Obrosova IG. (2010) Poly(ADP-ribose) polymerase-1 (PARP-1) gene deficiency alleviates diabetic kidney disease. Biochim. Biophys. Acta. 1802:1020–7.CrossRefGoogle Scholar
  24. 24.
    Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. (2011) Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press.Google Scholar
  25. 25.
    Hou A, et al. (2013) Rho GTPases and regulation of cell migration and polarization in human corneal epithelial cells. PLoS One. 8:e77107.CrossRefGoogle Scholar
  26. 26.
    Medici D, Potenta S, Kalluri R. (2011) Transforming growth factor-beta2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. Biochem. J. 437:515–20.CrossRefGoogle Scholar
  27. 27.
    Gao H, Zhang J, Liu T, Shi W. (2011) Rapamycin prevents endothelial cell migration by inhibiting the endothelial-to-mesenchymal transition and matrix metalloproteinase-2 and -9: an in vitro study. Mol. Vis. 17:3406–14.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Lee CH, et al. (2011) Ischemia-induced changes in glucagon-like peptide-1 receptor and neuroprotective effect of its agonist, exendin-4, in experimental transient cerebral ischemia. J. Neurosci. Res. 89:1103–13.CrossRefGoogle Scholar
  29. 29.
    Matsubara J, et al. (2012) A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J. Am. College Cardiol. 59:265–76.CrossRefGoogle Scholar
  30. 30.
    Ban K, et al. (2008) Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 117:2340–50.CrossRefGoogle Scholar
  31. 31.
    Bullock BP, Heller RS, Habener JF. (1996) Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology. 137:2968–78.CrossRefGoogle Scholar
  32. 32.
    Goumans MJ, van Zonneveld AJ, ten Dijke P. (2008) Transforming growth factor beta-induced endothelial-to-mesenchymal transition: a switch to cardiac fibrosis? Trends Cardiovasc. Med. 18:293–8.CrossRefGoogle Scholar
  33. 33.
    Kumarswamy R, et al. (2012) Transforming growth factor-beta-induced endothelial-to-mesenchymal transition is partly mediated by microRNA-21. Arterioscler. Thromb. Vasc. Biol. 32:361–9.CrossRefGoogle Scholar
  34. 34.
    Choi SK, et al. (2012) Poly(ADP-ribose) polymerase 1 inhibition improves coronary arteriole function in type 2 diabetes mellitus. Hypertension. 59:1060–8.CrossRefGoogle Scholar
  35. 35.
    Li WJ, Shin MK, Oh SJ. (2011) Poly(ADP-ribose) polymerase is involved in the development of diabetic cystopathy via regulation of nuclear factor kappa B. Urology. 77:1265.e1–8.Google Scholar
  36. 36.
    Rodriguez MI, et al. (2011) Poly(ADP-ribose)-dependent regulation of Snail1 protein stability. Oncogene. 30:4365–72.CrossRefGoogle Scholar
  37. 37.
    Shiraki A, et al. (2012) The glucagon-like peptide 1 analog liraglutide reduces TNF-alpha-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis. 221:375–82.CrossRefGoogle Scholar
  38. 38.
    Wang D, et al. (2013) Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes. 62:1697–708.CrossRefGoogle Scholar
  39. 39.
    Hendarto H, et al. (2012) GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metab. Clin. Exp. 61:1422–34.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  • Fei Yan
    • 1
    • 2
  • Guang-hao Zhang
    • 1
    • 3
  • Min Feng
    • 4
  • Wei Zhang
    • 1
  • Jia-ning Zhang
    • 5
  • Wen-qian Dong
    • 1
  • Cheng Zhang
    • 1
  • Yun Zhang
    • 1
  • Li Chen
    • 2
  • Ming-Xiang Zhang
    • 1
  1. 1.Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public HealthQilu Hospital of Shandong UniversityJinan, ShandongChina
  2. 2.Department of EndocrinologyQilu Hospital of Shandong UniversityJinan, ShandongChina
  3. 3.Department of CardiologyThe Second Hospital of Shandong UniversityJinanChina
  4. 4.Department of CardiologyAffiliated Hospital of Binzhou Medical UniversityBinzhou, ShandongChina
  5. 5.School of Foreign Languages and LiteratureShandong UniversityJinan, ShandongChina

Personalised recommendations