Journal of Molecular Histology

, Volume 49, Issue 6, pp 639–649 | Cite as

Favorable outcomes of metformin on coronary microvasculature in experimental diabetic cardiomyopathy

  • Ahmed A. M. Abdel-HamidEmail author
  • Alaa El-Din L. Firgany
Original Paper


Although metformin is widely prescribed in diabetes, its use with associated cardiac dysfunction remains debatable. In the current study, we investigated the effect of metformin on coronary microvasculature in experimental diabetic cardiomyopathy (DCM) induced by streptozotocin. Administration of metformin after induction of DCM, reversed almost all cardiomyocyte degenerative changes induced by DCM. Metformin diminished the significantly increased (p < 0.05) collagen deposited in the DCM. In addition metformin had improved the density of the significantly decreased arteriolar (αSMA+) and capillary (CD31+) coronary microvasculature compared to that of the DCM and non-diabetics (ND) with downregulation of the significantly increased expression (p < 0.05) of COL-I, III, TGF-β, CTGF, ICAM and VCAM genes. Therefore metformin may be beneficial in limiting the fibrotic and the vascular remodeling occurring in DCM at the genetic as well as the structural levels.


Metformin Diabetic cardiomyopathy Coronary microcirculation Vascular remodeling Fibrotic remodeling Cardiomyocyte steatosis 


Compliance with ethical standards

Conflict of interest

There is no conflict of interest regarding the current article.

Ethical approval

As we mentioned in the “Materials and methods” section, all procedures of the current experiment were approved by the Ethical Committee of Mansoura Faculty of Medicine.

Supplementary material

10735_2018_9801_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 KB)


  1. Abdel-Hamid AA, Firgany Ael D (2015) Atorvastatin alleviates experimental diabetic cardiomyopathy by suppressing apoptosis and oxidative stress. J Mol Histol 46:337–345CrossRefGoogle Scholar
  2. Abdel-Hamid AAM, Firgany Ael D (2016) Favorable outcomes of hydroxychloroquine in insulin resistance may be accomplished by adjustment of the endothelial dysfunction as well as the skewed balance of adipokines. Acta Histochem 118:560–573CrossRefGoogle Scholar
  3. Abdel-Hamid AA, Firgany AE, Mesbah Y et al (2016) Pattern of adhesive molecules expression in placenta of non-complicated ART pregnancies. Placenta 48:126–132CrossRefGoogle Scholar
  4. Ambasta RK, Kohli H, Kumar P (2017) Multiple therapeutic effect of endothelial progenitor cell regulated by drugs in diabetes and diabetes related disorder. J Transl Med 15:185CrossRefGoogle Scholar
  5. An H, He L (2016) Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Transl Med 228:R97–R106Google Scholar
  6. Apaijai N, Pintana H, Chattipakorn SC et al (2012) Cardioprotective effects of metformin and vildagliptin in adult rats with insulin resistance induced by a high-fat diet. Endocrinology 153:3878–3885CrossRefGoogle Scholar
  7. Apaijai N, Chinda K, Palee S et al (2014) Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats. PLoS ONE 9:e102374CrossRefGoogle Scholar
  8. Bakhashab S, Ahmed FW, Schulten HJ et al (2016) Metformin improves the angiogenic potential of human CD34(+) cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction. Cardiovasc Diabetol 15:27CrossRefGoogle Scholar
  9. Brown S, Worsfold M, Sharp C (2001) Microplate assay for the measurement of hydroxyproline in acid-hydrolyzed tissue samples. Biotechniques 30:38–40, 42CrossRefGoogle Scholar
  10. Chakraphan D, Sridulyakul P, Thipakorn B et al (2005) Attenuation of endothelial dysfunction by exercise training in STZ-induced diabetic rats. Clin Hemorheol Microcirc 32:217–226PubMedGoogle Scholar
  11. Dallaglio K, Bruno A, Cantelmo AR et al (2014) Paradoxic effects of metformin on endothelial cells and angiogenesis. Carcinogenesis 35:1055–1066CrossRefGoogle Scholar
  12. Duarte FO, Gomes-Gatto CDV (2017) Physical training improves visceral adipose tissue health by remodelling extracellular matrix in rats with estrogen absence: a gene expression analysis. Int J Exp Pathol 98:203–213CrossRefGoogle Scholar
  13. Forcheron F, Basset A, Abdallah P et al (2009) Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model–the Zucker diabetic rat. Cardiovasc Diabetol 8:16CrossRefGoogle Scholar
  14. Franssen C, Chen S, Unger A et al (2016) Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail 4:312–324CrossRefGoogle Scholar
  15. Hag AMF, Kristoffersen US, Pedersen SF et al (2009) Regional Gene Expression of LOX-1, VCAM-1, and ICAM-1 in Aorta of HIV-1 Transgenic Rats. PLoS ONE 4(12):e8170CrossRefGoogle Scholar
  16. Joe SG, Yoon YH, Choi JA et al (2015) Anti-angiogenic effect of metformin in mouse oxygen-induced retinopathy is mediated by reducing levels of the vascular endothelial growth factor receptor Flk-1. PLoS ONE 10:e0119708CrossRefGoogle Scholar
  17. Matyas C, Nemeth BT, Olah A et al (2017) Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes. Eur J Heart Fail 19:326–336CrossRefGoogle Scholar
  18. Meagher P, Adam M, Civitarese R et al (2018) Heart failure with preserved ejection fraction in diabetes: mechanisms and management. Can J Cardiol 34:632–643CrossRefGoogle Scholar
  19. Nesti L, Natali A (2017) Metformin effects on the heart and the cardiovascular system: a review of experimental and clinical data. Nutr Metabol Cardiovasc Dis 27:657–669CrossRefGoogle Scholar
  20. Paulus WJ, Dal Canto E (2018) Distinct myocardial targets for diabetes therapy in heart failure with preserved or reduced ejection fraction. JACC Heart Fail 6:1–7CrossRefGoogle Scholar
  21. Paulus WJ, Tschope C (2013) A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 62:263–271CrossRefGoogle Scholar
  22. Seferovic PM, Paulus WJ (2015) Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J 36:1718–1727, 1727a–1727cCrossRefGoogle Scholar
  23. Shida T, Nozawa T, Sobajima M et al (2014) Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature. Heart Vessels 29:532–541CrossRefGoogle Scholar
  24. Sivasinprasasn S, Sa-Nguanmoo P, Pongkan W et al (2016) Estrogen and DPP4 inhibitor, but not metformin, exert cardioprotection via attenuating cardiac mitochondrial dysfunction in obese insulin-resistant and estrogen-deprived female rats. Menopause 23:894–902CrossRefGoogle Scholar
  25. Sun J, Du J, Feng W et al (2017) Histological evidence that metformin reverses the adverse effects of diabetes on orthodontic tooth movement in rats. J Mol Histol 48:73–81CrossRefGoogle Scholar
  26. Tanajak P, Sa-Nguanmoo P, Apaijai N et al (2017) Comparisons of cardioprotective efficacy between fibroblast growth factor 21 and dipeptidyl peptidase-4 inhibitor in prediabetic rats. Cardiovasc Ther 35:e12263CrossRefGoogle Scholar
  27. Tschope C, Walther T, Koniger J et al (2004) Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB J 18:828–835CrossRefGoogle Scholar
  28. Tschope C, Walther T, Escher F et al (2005) Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J 19:2057–2059CrossRefGoogle Scholar
  29. Van Linthout S, Riad A, Dhayat N et al (2007) Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy. Diabetologia 50:1977–1986CrossRefGoogle Scholar
  30. Van Linthout S, Seeland U, Riad A et al (2008) Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 103:319–327CrossRefGoogle Scholar
  31. Xie Z, Lau K, Eby B et al (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60:1770–1778CrossRefGoogle Scholar
  32. Yu JW, Deng YP, Han X et al (2016) Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice. Cardiovasc Diabetol 15:88CrossRefGoogle Scholar
  33. Zhang Q, Xiao X, Zheng J et al (2018) Liraglutide protects cardiac function in diabetic rats through the PPARalpha pathway. Biosci Rep. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Zhao T, Luo D, Sun Y et al (2018) Human urine-derived stem cells play a novel role in the treatment of STZ-induced diabetic mice. J Mol Histol 49:419–428CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Ahmed A. M. Abdel-Hamid
    • 1
    Email author
  • Alaa El-Din L. Firgany
    • 1
  1. 1.Department of Histology and Cell Biology, Faculty of MedicineMansoura UniversityMansouraEgypt

Personalised recommendations