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Exp Clin Endocrinol Diabetes 2021; 129(12): 899-907
DOI: 10.1055/a-1162-8196
Article

Liraglutide Effect on Ventricular Transient Outward K +  Channel and Connexin-43 Protein Expression

Nehal M. Ramadan
1   Department of Clinical Pharmacology, Mansoura University, Faculty of Medicine, Mansoura, Egypt
,
Hala Abdel Malek
1   Department of Clinical Pharmacology, Mansoura University, Faculty of Medicine, Mansoura, Egypt
,
Karawan Abd-el Rahman
1   Department of Clinical Pharmacology, Mansoura University, Faculty of Medicine, Mansoura, Egypt
,
Elhamy El-Kholy
1   Department of Clinical Pharmacology, Mansoura University, Faculty of Medicine, Mansoura, Egypt
,
Dalia Shaalan
2   Departments of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
,
Wagdi Elkashef
3   Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Abstract

Background Human glucagon-like peptide-1 analogue, Liraglutide, has shown cardioprotective effects in animal and clinical studies of type 2 diabetes mellitus. This study was conducted to assess the effect of Liraglutide on diabetes-induced myocardial electrical remodeling.

Materials and Methods A rat model of type 2 diabetes mellitus was induced by high-fat diet and low dose Streptozotocin (35 mg/kg). Diabetic rats were randomized into 4 subgroups (n=6–7): diabetic-untreated, diabetics treated with Liraglutide, diabetics treated with Ramipril, and diabetics treated with Metformin in addition to a control group. Changes in serum glucose, insulin, lipid profile and revised quantitative insulin sensitivity check index (QUICKI index) were assessed. QT and QTc intervals were measured and the degree of cardiac interstitial and perivascular fibrosis was examined. The expression of myocardial Ito channel α subunits, gap junction protein; Kv 4.2/4.3 and connexin 43 (Cx43) respectively, were assessed by western blotting and immunohistochemistry.

Results Similar to Ramipril, both Liraglutide and Metformin effectively inhibited the diabetes-induced myocardial hypertrophy and fibrosis. However, Liraglutide treatment significantly improved Kv 4.2/4.3 and Cx43 expression/distribution and prevented diabetes-related QTc interval prolongation.

Conclusions We have shown that pathological alterations in myocardial Cx43 expression and distribution, in addition to reduced Ito channel expression, may underlie the QTc interval prolongation in high-fat diet/STZ rat model of type 2 diabetes mellitus. The beneficial effects of Liraglutide, as those of Ramipril, on cardiac electrophysiology could be at least attributed to its direct ability to normalize expression and distribution of Cx43 and Ito channels in the diabetic rat heart.

Key words

Liraglutide - myocardial remodeling - QTc - Ito channel - Cx43

Supplementary Material



Publication History

Received: 24 February 2019
Received: 11 April 2020

Accepted: 17 April 2020

Article published online:
19 June 2020

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Wold LE, Ceylan-Isik AF, Ren J. Oxidative stress and stress signaling: Menace of diabetic cardiomyopathy. Acta Pharmacol Sin 2005; 26: 908-917
    CrossrefPubMedGoogle Scholar
  • 2 US Food and Drug Administration. Guidance for Industry. Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available via: http://www.fda.gov/downloads/Drugs/guidanceComplianceRegulatoryInformation/guidances/ucm071627.pdf Accessed March 21, 2017
    PubMed
  • 3 Malm-Erjefält M, Bjørnsdottir I, Vanggaard J. et al. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase iv and neutral endopeptidase. DMD 2010; 38: 1944-1953
    CrossrefPubMedGoogle Scholar
  • 4 Noyan-Ashraf MH, Momen MA, Ban K. et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009; 58: 975-983
    CrossrefPubMedGoogle Scholar
  • 5 Chen WR, Chen YD, Tian F. et al. Effects of liraglutide on reperfusion injury in patients with ST-segment–elevation myocardial infarction. Circ Cardiovasc Imaging 2016; 9: e005146
    CrossrefPubMedGoogle Scholar
  • 6 Marso SP, Daniels GH, Brown-Frandsen K. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-322
    CrossrefPubMedGoogle Scholar
  • 7 Cutler MJ, Jeyaraj D, Rosenbaum DS. Cardiac electrical remodeling in health and disease. Trends Pharmacol Sci 2011; 32: 174-180
    CrossrefPubMedGoogle Scholar
  • 8 Nattel S. Defining “culprit mechanisms” in arrhythmogenic cardiac remodeling. Circ Res 2004; 94: 1403-1405
    CrossrefPubMedGoogle Scholar
  • 9 Lin H, Ogawa K, Imanaga I. et al. Remodeling of connexin 43 in the diabetic rat heart. Mol Cell Biochem 2006; 290: 69-78
    CrossrefPubMedGoogle Scholar
  • 10 Shimoni Y. Inhibition of the formation or action of angiotensin II reverses attenuated K+ currents in type 1 and type 2 diabetes. J Physiol 2001; 537: 83-92
    CrossrefPubMedGoogle Scholar
  • 11 Shimoni Y, Liu XF. Role of PKC in autocrine regulation of rat ventricular K+ currents by angiotensin and endothelin. Am J Physiol Heart Circ Physiol 2003; 284: H1168-H1181
    CrossrefPubMedGoogle Scholar
  • 12 Srinivasan K, Viswanad B, Asrat L. et al. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening. Pharmacol Res 2005; 52: 313-320
    CrossrefPubMedGoogle Scholar
  • 13 Raun K, von Voss P, Gotfredsen CF. et al. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007; 56: 8-15
    CrossrefPubMedGoogle Scholar
  • 14 Castoldi G, di Gioia CR, Bombardi C. et al. Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats. Clin Sci (Lond) 2010; 118: 211-220
    CrossrefPubMedGoogle Scholar
  • 15 Kmecova J, Klimas J. Heart rate correction of the QT duration in rats. Eur J Pharmacol 2010; 641: 187-192
    CrossrefPubMedGoogle Scholar
  • 16 Katz A, Nambi SS, Mather K. et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000; 85: 2402-2410
    CrossrefPubMedGoogle Scholar
  • 17 Iqbal J, Tonta MA, Mitsui R. et al. Potassium and ANO1/ TMEM16A chloride channel profiles distinguish atypical and typical smooth muscle cells from interstitial cells in the mouse renal pelvis. Br J Pharmacol 2012; 165: 2389-2408
    CrossrefPubMedGoogle Scholar
  • 18 Li C, Meng Q, Yu X. et al. Regulatory effect of connexin 43 on basal Ca2+ signaling in rat ventricular myocytes. PLoS One. 2012; 7: e36165
    CrossrefPubMedGoogle Scholar
  • 19 Howarth FC, Al-Sharhan R, Al-Hammadi A. et al. Effects of streptozotocin-induced diabetes on action potentials in the sinoatrial node compared with other regions of the rat heart. Mol Cell Biochem 2007; 300: 39-46
    CrossrefPubMedGoogle Scholar
  • 20 Tate M, Chong A, Robinson E. et al. Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes. Br J Pharmacol 2015; 172: 721-736
    CrossrefPubMedGoogle Scholar
  • 21 Ouyang C, You J, Xie Z. The interplay between autophagy and apoptosis in the diabetic heart. J Mol Cell Cardiol 2014; 71: 71-80
    CrossrefPubMedGoogle Scholar
  • 22 Monji A, Mitsui T, Bando YK. et al. 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 2013; 305: 295-304
    CrossrefPubMedGoogle Scholar
  • 23 Wang D, Luo P, Wang Y. et al. Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes 2013; 62: 1697-1708
    CrossrefPubMedGoogle Scholar
  • 24 Inoue T, Inoguchia T, Sonoda N. et al. GLP-1 analog liraglutide protects against cardiac steatosis, oxidative stress and apoptosis in streptozotocin-induced diabetic rats. Atherosclerosis 2015; 240: 250-259
    CrossrefPubMedGoogle Scholar
  • 25 Yu W, Zha W, Ren J. Exendin-4 and liraglutide attenuate glucose toxicity-induced cardiac injury through mTOR/ULK1-dependent autophagy. Oxid Med Cell Longev 2018; 2018; 5396806
    PubMed
  • 26 Gaspari T, Brdar M, Lee HW. et al. Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis. Diabetes and Vascular Disease Research 2016; 13: 56-68
    CrossrefPubMedGoogle Scholar
  • 27 Adebiyi OA, Adebiyi OO, Owira PMO. Naringin reduces hyperglycemia-induced cardiac fibrosis by relieving oxidative stress. PLoS One 2016; 11: e0149890
    CrossrefPubMedGoogle Scholar
  • 28 Ma F, Li Y, Jia L. et al. Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II. PLoS One 2012; 7: e35144
    CrossrefPubMedGoogle Scholar
  • 29 Lopez-Izquierdo A, Pereira RO, Wende AR. et al. The absence of insulin signaling in the heart induces changes in potassium channel expression and ventricular repolarization. Am. J. Physiol. Heart Circ. Physiol 2014; 306: 747-754
    CrossrefPubMedGoogle Scholar
  • 30 van Rijen HV, Eckardt D, Degen J. et al. Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation 2004; 109: 1048-1055
    CrossrefPubMedGoogle Scholar
  • 31 Mayama T, Matsumura K, Lin H. et al. Remodelling of cardiac gap junction connexin 43 and arrhythmogenesis. Exp Clin Cardiol 2007; 12: 67-76
    PubMedGoogle Scholar
  • 32 Noyan-Ashraf MH, Shikatani EA, Schuiki I. et al. A Glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation 2013; 127: 74-85
    CrossrefPubMedGoogle Scholar
  • 33 Morrow JP, Katchman A, Son NH. et al. Mice with cardiac overexpression of PPARγ have impaired repolarization and spontaneous fatal ventricular arrhythmias. Circulation 2011; 124: 2812-2821
    CrossrefPubMedGoogle Scholar
  • 34 Gussak I, Chaitman BR, Kopecky SL. et al. Rapid ventricular repolarization in rodents: electrocardiographic manifestations, molecular mechanisms, and clinical insights. J Electrocardiol 2000; 33: 159-170
    CrossrefPubMedGoogle Scholar
  • 35 Shimoni Y, Firek L, Severson D. et al. Short-term diabetes alters K+ currents in rat ventricular myocytes. Circ Res 1994; 74: 620-628
    CrossrefPubMedGoogle Scholar
  • 36 Shimoni Y, Ewart HS, Severson D. Insulin stimulation of rat ventricular K+ currents depends on the integrity of the cytoskeleton. J. Physiol 1999; 514: 735-745
    CrossrefPubMedGoogle Scholar
  • 37 Marionneau C, Aimond F, Brunet S. et al. PPARα-mediated remodeling of repolarizing voltage-gated K+ (Kv) channels in a mouse model of metabolic cardiomyopathy. J Mol Cell Cardiol 2008; 44: 1002-1015
    CrossrefPubMedGoogle Scholar
  • 38 Eranti A, Kerola T, Aro AL. et al. Diabetes, glucose tolerance, and the risk of sudden cardiac death. BMC Cardiovascular Disorders 2016; 16: 51
    CrossrefPubMedGoogle Scholar
  • 39 Howarth FC, Jacobson M, Qureshi MA. et al. Altered gene expression may underlie prolonged duration of the QT interval and ventricular action potential in streptozotocin- induced diabetic rat heart. Mol Cell Biochem 2009; 328: 57-65
    CrossrefPubMedGoogle Scholar
  • 40 Hattori Y, Hattori K, Suzuki T. Differential modulation of cardiac sympathetic neural control and β-Adrenoceptor-G protein signaling cascade in rats with type 1 and type 2 diabetes. Diabetes 2015; 64: 2708-2710
    CrossrefPubMedGoogle Scholar
  • 41 Meier JJ, Rosenstock J, Hincelin-Méry A. et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: A randomized, open-label trial. Diabetes Care 2015; 38: 1263-1273
    CrossrefPubMedGoogle Scholar
  • 42 Hara K, Aso Y, Komatsu T. et al. Liraglutide increases 24-h heart rate by reducing the cardiac parasympathetic activity of patients with type 2 diabetes: Power spectral analysis of heart rate variability on 24-h Holter ECG recordings. Diabetol Int 2014; 6: 26-32
    CrossrefPubMedGoogle Scholar