Skip to main content
SpringerLink
Log in

Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonin and omega-3 fatty acids in female rats

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

We aimed to explore whether specific high-sucrose intake in older female rats affects myocardial electrical coupling protein, connexin-43 (Cx43), protein kinase C (PKC) signaling, miR-1 and miR-30a expression, and susceptibility of the heart to malignant arrhythmias. Possible benefit of the supplementation with melatonin (40 µg/ml/day) and omega-3 polyunsaturated fatty acids (Omacor, 25 g/kg of rat chow) was examined as well. Results have shown that 8 weeks lasting intake of 30% sucrose solution increased serum cholesterol, triglycerides, body weight, heart weight, and retroperitoneal adipose tissues. It was accompanied by downregulation of cardiac Cx43 and PKCε signaling along with an upregulation of myocardial PKCδ and miR-30a rendering the heart prone to ventricular arrhythmias. There was a clear benefit of melatonin or omega-3 PUFA supplementation due to their antiarrhythmic effects associated with the attenuation of myocardial Cx43, PKC, and miR-30a abnormalities as well as adiposity. The potential impact of these findings may be considerable, and suggests that high-sucrose intake impairs myocardial signaling mediated by Cx43 and PKC contributing to increased susceptibility of the older obese female rat hearts to malignant arrhythmias.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Saffitz JE (2006) Douglas P. zipes lecture. Biology and pathobiology of cardiac connexins: from cell to bedside. Heart Rhythm 3:102–107. https://doi.org/10.1016/j.hrthm.2005.10.021

    Article  PubMed  Google Scholar 

  2. Severs NJ (2001) Gap junction remodelling and cardiac arrhythmogenesis: cause or coincidence? J Cell Mol Med 5:355–366

    Article  CAS  PubMed  Google Scholar 

  3. Poelzing S, Akar FG, Baron E, Rosenbaum DS (2004) Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall. Am J Physiol Heart Circ Physiol 286:2001–2009. https://doi.org/10.1152/ajpheart.00987.2003

    Article  Google Scholar 

  4. Danik SB, Liu F, Zhang J, Suk HJ, Morley GE, Fishman GI, Gutstein DE (2004) Modulation of cardiac gap junction expression and arrhythmic susceptibility. Circ Res 95:1035–1041. https://doi.org/10.1161/01.RES.0000148664.33695.2a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tribulova N, Szeiffova Bacova B, Benova T et al (2015) Can we protect from malignant arrhythmias by modulation of cardiac cell-to-cell coupling? J Electrocardiol 48:434–440

    Article  PubMed  Google Scholar 

  6. Tribulova N, Egan Benova T, Szeiffova Bacova B, Viczenczova C (2015) New aspects of pathogenesis of atrial fibrillation: remodelling of intercalated discs. J Physiol Pharmacol 66:625–634. https://doi.org/10.1016/j.jelectrocard.2015.02.006

    Article  CAS  PubMed  Google Scholar 

  7. Bačová BS, Vinczenzová C, Žurmanová J, Kašparová D, Knezl V, Beňová TE, Pavelka S, Soukup T, Tribulová N (2017) Altered thyroid status affects myocardial expression of connexin-43 and susceptibility of rat heart to malignant arrhythmias that can be partially normalized by red palm oil intake. Histochem Cell Biol 147:63–73. https://doi.org/10.1007/s00418-016-1488-6

    Article  CAS  PubMed  Google Scholar 

  8. Lin H, Mitasikova M, Dlugosova K, Okruhlicova L, Imanaga I, Ogawa K, Weismann P, Tribulova N (2008) Thyroid hormones suppress epsilon-PKC signalling, down-regulate connexin-43 and increase lethal arrhythmia susceptibility in non-diabetic and diabetic rat hearts. J Physiol Pharmacol 59:271–285

    CAS  PubMed  Google Scholar 

  9. Saitongdee P, Milner P, Becker DL, Knight GE, Burnstock G (2000) Increased connexin43 gap junction protein in hamster cardiomyocytes during cold acclimatization and hibernation. Cardiovasc Res 47:108–115

    Article  CAS  PubMed  Google Scholar 

  10. Nielsen MS, Axelsen LN, Sorgen PL, Verma V, Delmar M, Holstein-Rathlou NH (2012) Gap junctions. Compr Physiol 2:1981–2035. https://doi.org/10.1002/cphy.c110051

    Article  PubMed  Google Scholar 

  11. Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G, Wang Z (2007) The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med 13:486. https://doi.org/10.1038/nm1569

    Article  CAS  PubMed  Google Scholar 

  12. Pan W, Zhong Y, Cheng C, Liu B, Wang L, Li A, Xiong L, Liu S (2013) MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy. PLoS ONE 8:e53950. https://doi.org/10.1371/journal.pone.0053950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Duisters RF, Tijsen AJ, Schroen B, Leenders JJ, Lentink V, van der Made I, Herias V, van Leeuwen RE, Schellings MW, Barenbrug P, Maessen JG, Heymans S, Pinto YM, Creemers EE (2009) miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res 104:170–178. https://doi.org/10.1161/CIRCRESAHA.108.182535

    Article  CAS  PubMed  Google Scholar 

  14. Vos MB, Kaar JL, Welsh JA, Van Horn LV, Feig DI, Anderson CAM, Patel MJ, Cruz Munos J, Krebs NF, Xanthakos SA, Johnson RK (2017) Added sugars and cardiovascular disease risk in children: a scientific statement from the American Heart Association. Circulation 135:e1017–e1034. https://doi.org/10.1161/CIR.0000000000000439

    Article  CAS  PubMed  Google Scholar 

  15. Maury E, Ramsey KM, Bass J (2011) Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circ Res 106:447–462. https://doi.org/10.1161/CIRCRESAHA.109.208355

    Article  CAS  Google Scholar 

  16. Nduhirabandi F, du Toit EF, Lochner A (2012) Melatonin and the metabolic syndrome: a tool for effective therapy in obesity-associated abnormalities? Acta Physiol (Oxf) 205:209–223. https://doi.org/10.1111/j.1748-1716.2012.02410.x

    Article  CAS  Google Scholar 

  17. Pathak RK, Mahajan R, Lau DH, Sanders P (2015) The implications of obesity for cardiac arrhythmia mechanisms and management. Can J Cardiol 31(2):203–210. https://doi.org/10.1016/j.cjca.2014.10.027

    Article  PubMed  Google Scholar 

  18. Bonnefont-Rousselot D (2014) Obesity and oxidative stress: potential roles of melatonin as antioxidant and metabolic regulator. Endocr Metab Immune Disord Drug Targets 14:159–168

    Article  CAS  PubMed  Google Scholar 

  19. Yang KC, Kyle JW, Makielski JC, Dudley SC Jr (2015) Mechanisms of sudden cardiac death: oxidants and metabolism. Circ Res 116:1937–1955. https://doi.org/10.1161/CIRCRESAHA.116.3046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lalani AP, Kanna B, John J, Ferrick KJ, Huber MS, Shapiro LE (2000) Abnormal signal-averaged electrocardiogram (SAECG) in obesity. Obes Res 8:20–28. https://doi.org/10.1038/oby.2000.4

    Article  CAS  PubMed  Google Scholar 

  21. Rothe S, Busch A, Bittner H, Kostelka M, Dohmen PM, Mohr FW, Dhein S (2014) Body mass index affects connexin43 remodeling in patients with atrial fibrillation. Thorac Cardiovasc Surg 62(7):547–553. https://doi.org/10.1055/s-0034-1372334

    Article  PubMed  Google Scholar 

  22. Meng T, Cheng G, Wei Y, Ma S, Jiang Y, Wu J, Zhou X, Sun C (2017) Exposure to a chronic high-fat diet promotes atrial structure and gap junction remodeling in rats. Int J Mol Med 40(1):217–225. https://doi.org/10.3892/ijmm.2017.2982

    Article  CAS  PubMed  Google Scholar 

  23. Nalliah CJ, Sanders P, Kottkamp H, Kalman JM (2016) The role of obesity in atrial fibrillation. Eur Heart J 37(20):1565–1572. https://doi.org/10.1093/eurheartj/ehv486

    Article  PubMed  Google Scholar 

  24. Bernasochi GB, Boon WC, Curl CL, Varma U, Pepe S, Tare M, Parry LJ, Dimitriadis E, Harrap SB, Nalliah CJ, Kalman JM, Delbridge LMD, Bell JR (2017) Pericardial adipose and aromatase: a new translational target for aging, obesity and arrhythmogenesis? J Mol Cell Cardiol 111:96–101. https://doi.org/10.1016/j.yjmcc.2017.08.006

    Article  CAS  PubMed  Google Scholar 

  25. Cipolla-neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ (2014) Melatonin, energy metabolism, and obesity: a review. J Pineal Res 56:371–381. https://doi.org/10.1111/jpi.12137

    Article  CAS  PubMed  Google Scholar 

  26. Zhang L, Su P, Xu C, Chen C, Liang A, Du K, Peng Y, Huang D (2010) Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARc expression and enhancing Runx2 expression. J Pineal Res 49:364–372. https://doi.org/10.1111/j.1600-079X.2010.00803.x

    Article  CAS  PubMed  Google Scholar 

  27. Lavie CJ, Milani RV, Ventura HO (2009) Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 53:1925–1932. https://doi.org/10.1016/j.jacc.2008.12.068

    Article  PubMed  Google Scholar 

  28. Benova T, Viczenczova C, Radosinska J, Bacova B, Knezl V, Dosenko V, Weismann P, Zeman M, Navarova J, Tribulova N (2013) Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias. Can J Physiol Pharmacol 91:633–639. https://doi.org/10.1139/cjpp-2012-0393

    Article  CAS  PubMed  Google Scholar 

  29. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61:253–278. https://doi.org/10.1111/jpi.12360

    Article  CAS  PubMed  Google Scholar 

  30. Sovari AA, Rutledge CA, Jeong EM, Dolmatova E, Arasu D, Liu H, Vahdani N, Gu L, Zandieh S, Xiao L, Bonini MG, Duffy HS, Dudley SC Jr (2013) Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death. Circ Arrhythm Electrophysiol 6:623–631. https://doi.org/10.1161/CIRCEP.112.976787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Von Schacky C, Harris WS (2007) Cardiovascular risk and the omega-3 index. J Cardiovasc Med 8:46–49. https://doi.org/10.2459/01.JCM.0000289273.87803.87

    Article  Google Scholar 

  32. Tribulova N, Szeiffova Bacova B, Egan Benova T, Knezl V, Barancik M, Slezak J (2017) Omega-3 index and anti-arrhythmic potential of omega-3 PUFAs. Nutrients 9:E1191. https://doi.org/10.3390/nu9111191

    Article  CAS  PubMed  Google Scholar 

  33. Mitašíková M, Šmidová S, Macsaliová A, Knezl V, Dlugosová K, Okruhlicová L, Weismann P, Tribulová N (2008) Aged male and female spontaneously hypertensive rats benefit from n-3 polyunsaturated fatty acids supplementation. Physiol Res 57:39–48

    Google Scholar 

  34. Benova T, Knezl V, Viczenczova C, Bacova BS, Radosinska J, Tribulova N (2015) Acute anti-fibrillating and defibrillating potential of atorvastatin, melatonin, eicosapentaenoic acid and docosahexaenoic acid demonstrated in isolated heart model. J Physiol Pharmacol 66:83–89

    CAS  PubMed  Google Scholar 

  35. Kramer JH, Murthi SB, Wise SB, Mak IT, Weglicki WB (2006) Antioxidant and lysosomotropic properties of acute d-propranolol underlies its cardioprotection of postischemic hearts from moderate iron-overloaded rats. Exp Biol Med (Maywood) 231:473–484

    Article  CAS  Google Scholar 

  36. Stebelová K, Herichová I, Zeman M (2007) Diabetes induces changes in melatonin concentrations in peripheral tissues of rat. Neuro Endocrinol Lett 28:159–165

    PubMed  Google Scholar 

  37. Dosenko VE, Gurianova VL, Surova OV, Stroy DA, Moibenko AA (2012) Mature and immature microRNA ratios in cultured rat cardiomyocytes during anoxia-reoxygenation. Exp Clin Cardiol 17:84–87

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tran LT, Yuen VG, McNeill JH (2009) The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem 332:145–159. https://doi.org/10.1007/s11010-009-0184-4

    Article  CAS  PubMed  Google Scholar 

  39. Demirtas CY, Pasaoglu OT, Bircan FS, Kantar S, Turkozkan N (2015) The investigation of melatonin effect on liver antioxidant and oxidant levels in fructose-mediated metabolic syndrome model. Eur Rev Med Pharmacol Sci 19:1915–1921

    CAS  PubMed  Google Scholar 

  40. Gupta AK, Johnson WD, Johannsen D, Ravussin E (2013) Cardiovascular risk escalation with caloric excess: a prospective demonstration of the mechanics in healthy adults. Cardiovasc Diabetol 12:23. https://doi.org/10.1186/1475-2840-12-23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bender N, Portmann M, Heg Z, Hofmann K, Zwahlen M, Egger M (2014) Fish or n3-PUFA intake and body composition: a systematic review and meta-analysis. Obes Rev 15:657–665. https://doi.org/10.1111/obr.12189

    Article  CAS  PubMed  Google Scholar 

  42. Xu P, Wang J, Hong F, Wang S, Jin X, Xue T, Jia L, Zhai Y (2017) Melatonin prevents obesity through modulation of gut microbiota in mice. J Pineal Res. https://doi.org/10.1111/jpi.12399

    Article  PubMed  Google Scholar 

  43. Mesri Alamdari N, Mahdavi R, Roshanravan N, Lotfi Yaghin N, Ostadrahimi AR, Faramarzi EA (2015) Double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm Metab Res 47:504–508. https://doi.org/10.1055/s-0034-1384587

    Article  CAS  PubMed  Google Scholar 

  44. Froy O (2007) The relationship between nutrition and circadian rhythms in mammals. Front Neuroendocrinol 28:61–71. https://doi.org/10.1016/j.yfrne.2007.03.001

    Article  CAS  PubMed  Google Scholar 

  45. Hatem SN, Redheuil A, Gandjbakhch E (2016) Cardiac adipose tissue and atrial fibrillation: the perils of adiposity. Cardiovasc Res 109:502–509. https://doi.org/10.1093/cvr/cvw001

    Article  CAS  PubMed  Google Scholar 

  46. Lee JJ, Yin X, Hoffmann U, Fox CS, Benjamin EJ (2016) Relation of pericardial fat, intrathoracic fat, and abdominal visceral fat with incident atrial fibrillation (from the Framingham Heart Study). Am J Cardiol 118:1486–1492. https://doi.org/10.1016/j.amjcard.2016.08.011

    Article  PubMed  PubMed Central  Google Scholar 

  47. Aubin MC, Cardin S, Comtois P, Clément R, Gosselin H, Gillis MA, Le Quang K, Nattel S, Perrault LP, Calderone A (2010) A high-fat diet increases risk of ventricular arrhythmia in female rats: enhanced arrhythmic risk in the absence of obesity or hyperlipidemia. J Appl Physiol 108(4):933–933. https://doi.org/10.1152/japplphysiol.01281.2009

    Article  PubMed  Google Scholar 

  48. Diez ER, Renna NF, Prado NJ, Lembo C, Zumino AZP, Vazquez-Prieto M, Miatello RM (2013) Melatonin, given at the time of reperfusion, prevents ventricular arrhythmias in isolated hearts from fructose-fed rats and spontaneously hypertensive rats. J Pineal Res 55:166–173. https://doi.org/10.1111/jpi.12059

    Article  CAS  PubMed  Google Scholar 

  49. Lennon-Edwards S, Schellhardt TA, Kuczmarski JM (2015) Antioxidant defense is increased in aged hearts following omega-3 supplementation in the absence of changes in inflammation. Physiol Res 64:433–438

    CAS  PubMed  Google Scholar 

  50. Bertuglia S, Reiter RJ (2007) Melatonin reduces ventricular arrhythmias and preserves capillary perfusion during ischemia-reperfusion events in cardiomyopathic hamsters. J Pineal Res 42:55–63. https://doi.org/10.1111/j.1600-079X.2006.00383.x

    Article  CAS  PubMed  Google Scholar 

  51. Leaf A, Kang JX, Xiao YF, Billman GE (2003) Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 107:2646–2652. https://doi.org/10.1161/01.CIR.0000069566.78305.33

    Article  PubMed  Google Scholar 

  52. Cha MJ, Oh S (2013) The relationship between pericardial fat and atrial fibrillation. J Atr Fibrillation 5:676. https://doi.org/10.4022/jafib.676

    Article  PubMed  PubMed Central  Google Scholar 

  53. Jeyaraman MM, Srisakuldee W, Nickel BE, Kardami E (2012) Connexin43 phosphorylation and cytoprotection in the heart. Biochim Biophys Acta 1818:2009–2013. https://doi.org/10.1016/j.bbamem.2011.06.023

    Article  CAS  PubMed  Google Scholar 

  54. Doble BW, Ping P, Kardami E (2000) The epsilon subtype of protein kinase C is required for cardiomyocyte connexin-43 phosphorylation. Circ Res 86:293–301

    Article  CAS  PubMed  Google Scholar 

  55. Radosinska J, Bacova B, Knezl V, Benova T, Zurmanova J, Soukup T, Arnostova P, Slezak J, Gonçalvesova E, Tribulova N (2013) Dietary omega-3 fatty acids attenuate myocardial arrhythmogenic factors and propensity of the heart to lethal arrhythmias in a rodent model of human essential hypertension. J Hypertens 31:1876–1885. https://doi.org/10.1097/HJH.0b013e328362215d

    Article  CAS  PubMed  Google Scholar 

  56. Dhein S, Hagen A, Jozwiak J, Dietze A, Garbade J, Barten M, Kostelka M, Mohr FW (2010) Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn Schmiedebergs Arch Pharmacol 381(3):221–234. https://doi.org/10.1007/s00210-009-0473-1

    Article  CAS  PubMed  Google Scholar 

  57. Steinberg S (2004) Distinctive activation mechanisms and functions for protein kinase C delta. Biochem J 384:449–459. https://doi.org/10.1042/BJ20040704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by APVV-15-0119, Slovak Cardiological Society Grant and VEGA 2/0167/15, 2/0076/16 grants, and by EU Structural Fund ITMS 26230120006. Omacor was kindly provided by Dr. Branislav Obsitnik from Abbott laboratories, Slovakia. English editing was performed by Drs. Vladislava Zoldi and RJ. Reitter.

Author information

Authors and Affiliations

  1. Center of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04, Bartislava, Slovakia

    Tamara Egan Benova, Csilla Viczenczova, Barbara Szeiffova Bacova & Narcis Tribulova

  2. Center of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia

    Vladimir Knezl

  3. State Key Laboratory of Molecular and Cellular Biology, Bogomoletz Institute of Physiology, Kyiv, Ukraine

    Victor Dosenko

  4. Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic

    Hana Rauchova

  5. Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia

    Michal Zeman

  6. Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, 78229, TX, USA

    Russel J. Reiter

Authors
  1. Tamara Egan Benova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Csilla Viczenczova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Szeiffova Bacova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vladimir Knezl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Victor Dosenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hana Rauchova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michal Zeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Russel J. Reiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Narcis Tribulova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Narcis Tribulova.

Ethics declarations

Conflict of interest

There is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Egan Benova, T., Viczenczova, C., Szeiffova Bacova, B. et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonin and omega-3 fatty acids in female rats. Mol Cell Biochem 454, 191–202 (2019). https://doi.org/10.1007/s11010-018-3463-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3463-0

Keywords

Search

Navigation