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Increase in cardioprotective SUR2A does not alter heart rate and heart rate regulation by physical activity and diurnal rhythm

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Published/Copyright: December 3, 2021
Journal of Basic and Clinical Physiology and Pharmacology
From the journal Journal of Basic and Clinical Physiology and Pharmacology Volume 33 Issue 5

Abstract

Objectives

SUR2A is an ABC protein serving as a regulatory subunit of ATP-sensitive (KATP) channels. An increase in SUR2A levels is cardioprotective and it is a potential therapeutic strategy against ischaemic heart disease, heart failure and other diseases. However, whether overexpression of this protein has any adverse effects is yet to be fully understood. Here, we examined the heart rate and the heart rate diurnal variation in mice overexpressing SUR2A (SUR2A+) and their littermate controls (WT) using ECG telemetry that was continuously recorded for 14 days (days 8–23 post-radiotransmitter implantation).

Methods

Using SigmaPlot 14.0 and Microsoft Excel, Area Under the Curve (AUC) for each parameter was calculated and plotted in a graph.

Results

Both WT and SUR2A+ mice were more physically active during nights and there were no significant differences between two phenotypes. Physical activity was associated with increased heart rate in both phenotypes, but there were no differences in heart rate between phenotypes irrespective of physical activity or time of the day. A diurnal heart rate variation was preserved in the SUR2A+ mice. As area under the curve (AUC) analysis has the potential to reveal differences that are invisible with other statistical methods, we compared AUC of heart rate in SUR2A+ and WT mice. This analysis did not yield anything different from traditional analysis.

Conclusions

We conclude that increased SUR2A levels are not associated with changes in physical activity, heart rate and/or circadian rhythm influence on the heart rate. This lack of adverse effects supports a notion that manipulation with SUR2A levels is a promising cardioprotective strategy.

Keywords: cardioprotection; circadian rhythm; heart rate; physical activity; SUR2A
Corresponding author: Aleksandar Jovanović, Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus; and Center for Neuroscience and Integrative Brain Research (CENIBRE), University of Nicosia Medical School, Nicosia, Cyprus, Phone: +357 22 471 976, E-mail:

Funding source: British Heart Foundation

Award Identifier / Grant number: PG/11/106/29235

Award Identifier / Grant number: PG/15/28/31384

  1. Research funding: This work was supported by British Heart Foundation (grants no. PG/11/106/29235 and PG/15/28/31384).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: The experiments in this study have been done under authority of Project Licenses 60/3152 and 60/3925 approved by the Home Office (UK).

References

1. Mccraty, R, Shaffer, F. Heart rate variability: new perspectives on physiological mechanisms, Assessment of Self-regulatory Capacity, and Health Risk. Global Adv Health Med 2015;4:46–61. https://doi.org/10.7453/gahmj.2014.073.Search in Google Scholar PubMed PubMed Central

2. Hsieh, PN, Zhang, L, Jain, MK. Coordination of cardiac rhythmic output and circadian metabolic regulation in the heart. Cell Mol Life Sci 2017;75:403–16. https://doi.org/10.1007/s00018-017-2606-x.Search in Google Scholar PubMed PubMed Central

3. Soares, AC, Fonseca, DA. Cardiovascular diseases: a therapeutic perspective around the clock. Drug Discov Today 2020;25:1086–98. https://doi.org/10.1016/j.drudis.2020.04.006.Search in Google Scholar PubMed

4. Vandewalle, G, Middleton, B, Rajaratnam, SMW, Stone, BM, Thorleifsdottir, B, Arendt, J, et al.. Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod. J Sleep Res 2007;16:148–55. https://doi.org/10.1111/j.1365-2869.2007.00581.x.Search in Google Scholar PubMed

5. Cimen, B, Uz, A, Cetin, I, Cimen, L, Cetin, A. Melatonin supplementation ameliorates energy charge and oxidative stress induced by acute exercise in rat heart tissue. Acta Cardiol Sin;33:530–8. https://doi.org/10.6515/acs20170331a.Search in Google Scholar PubMed PubMed Central

6. Tinker, A, Aziz, Q, Li, Y, Specterman, M. ATP‐sensitive potassium channels and their physiological and pathophysiological roles. Compr Physiol 2018:1463–511. https://doi.org/10.1002/cphy.c170048.Search in Google Scholar PubMed

7. Du, Q, Jovanović, S, Clelland, A, Sukhodub, A, Budas, G, Phelan, K, et al.. Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia. FASEB J 2006;20:1131–41. https://doi.org/10.1096/fj.05-5483com.Search in Google Scholar PubMed PubMed Central

8. Jovanović, A. Cardioprotective signalling: past, present and future. Eur J Pharmacol 2018;833:314–9. https://doi.org/10.1016/j.ejphar.2018.06.029.Search in Google Scholar PubMed

9. Jovanović, A. SUR2A: How to exploit this protein to treat ischaemic heart disease? Arh Farm 2020;70:1–9.10.5937/arhfarm2001001JSearch in Google Scholar

10. Sudhir, R, Du, Q, Sukhodub, A, Jovanović, S, Jovanović, A. Improved adaptation to physical stress in mice overexpressing SUR2A is associated with changes in the pattern of Q-T interval. Pflügers Archiv Eur J Physiol 2020;472:683–91. https://doi.org/10.1007/s00424-020-02401-5.Search in Google Scholar PubMed PubMed Central

11. Sudhir, R, Sukhodub, A, Du, Q, Jovanović, S, Jovanović, A. Ageing-induced decline in physical endurance in mice is associated with decrease in cardiac SUR2A and increase in cardiac susceptibility to metabolic stress: therapeutic prospects for up-regulation of SUR2A. Biogerontology 2010;12:147–55. https://doi.org/10.1007/s10522-010-9306-3.Search in Google Scholar PubMed

12. Burgess, K, Jovanović, S, Sudhir, R, Jovanović, A. Area under the curve analysis of blood pressure reveals increased spontaneous locomotor activity in SPAK knock-in mice: relevance for hypotension induced by SPAK inhibition? Physiol Rep 2019;7:e13997. https://doi.org/10.14814/phy2.13997.Search in Google Scholar PubMed PubMed Central

13. Du, Q, Jovanović, S, Sukhodub, A, Jovanović, A. Infection with AV-SUR2A protects H9C2 cells against metabolic stress: a mechanism of SUR2A-mediated cytoprotection independent from the KATP channel activity. Biochim Biophys Acta Mol Cell Res 2010;1803:405–15. https://doi.org/10.1016/j.bbamcr.2010.01.018.Search in Google Scholar PubMed PubMed Central

14. Mohammed Abdul, KS, Jovanović, S, Sukhodub, A, Du, Q, Jovanović, A. Upregulation of cardioprotective SUR2A by sub-hypoxic drop in oxygen. Biochim Biophys Acta Mol Cell Res 2014;1843:2424–31. https://doi.org/10.1016/j.bbamcr.2014.07.007.Search in Google Scholar PubMed PubMed Central

15. Mohammed Abdul, KS, Jovanović, S, Jovanović, A. Exposure to 15% oxygen in vivo up-regulates cardioprotective SUR2A without affecting ERK1/2 and AKT: a crucial role for AMPK. J Cell Mol Med 2017;21:1342–50. https://doi.org/10.1111/jcmm.13064.Search in Google Scholar PubMed PubMed Central

16. Crawford, RM, Ranki, HJ, Botting, CH, Budas, GR, Jovanovic, A. Creatine kinase is physically associated with the cardiac ATP‐sensitive k + channel in vivo. FASEB J 2001;16:1–17. https://doi.org/10.1096/fj.01-0466fje.Search in Google Scholar PubMed PubMed Central

17. Jovanović, S, Du, Q, Crawford, RM, Budas, GR, Stagljar, I, Jovanović, A. Glyceraldehyde 3‐phosphate dehydrogenase serves as an accessory protein of the cardiac sarcolemmal K ATP channel. EMBO Rep 2005;6:848–52. https://doi.org/10.1038/sj.embor.7400489.Search in Google Scholar PubMed PubMed Central

18. Jovanović, S, Du, Q, Sukhodub, A, Jovanović, A. M-LDH physically associated with sarcolemmal KATP channels mediates cytoprotection in heart embryonic H9C2 cells. Int J Biochem Cell Biol 2009;41:2295–301. https://doi.org/10.1016/j.biocel.2009.05.012.Search in Google Scholar PubMed PubMed Central

19. Jovanović, S, Du, Q, Sukhodub, A, Jovanović, A. A dual mechanism of cytoprotection afforded by M-LDH in embryonic heart H9C2 cells. Biochim Biophys Acta Mol Cell Res 2009;1793:1379–86.10.1016/j.bbamcr.2009.04.007Search in Google Scholar PubMed PubMed Central

20. Sukhodub, A, Sudhir, R, Du, Q, Jovanović, S, Reyes, S, Jovanović, A. Nicotinamide-rich diet improves physical endurance by up-regulating SUR2A in the heart. J Cell Mol Med 2011;15:1703–12. https://doi.org/10.1111/j.1582-4934.2010.01156.x.Search in Google Scholar PubMed PubMed Central

21. Sukhodub, A, Du, Q, Jovanović, S, Jovanović, A. Nicotinamide-rich diet protects the heart against ischaemia–reperfusion in mice: a crucial role for cardiac SUR2A. Pharmacol Res 2010;61:564–70. https://doi.org/10.1016/j.phrs.2010.01.008.Search in Google Scholar PubMed PubMed Central

22. Sinha, S, Du, Q, Jovanović, S, Sukhodub, A, Jovanović, A. Pyrazinamide may possess cardioprotective properties. J Antibiot 2019;72:714–7. https://doi.org/10.1038/s41429-019-0202-z.Search in Google Scholar PubMed PubMed Central

23. Aziz, Q, Finlay, M, Montaigne, D, Ojake, L, Li, Y, Anderson, N, et al.. ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia. J Biol Chem 2018;293:8912–21. https://doi.org/10.1074/jbc.ra118.002775.Search in Google Scholar

24. Zhao, D, Yu, Y, Shen, Y, Liu, Q, Zhao, Z, Sharma, R, et al.. Melatonin synthesis and function: evolutionary history in animals and plants. Front Endocrinol;10:249. https://doi.org/10.3389/fendo.2019.00249.Search in Google Scholar PubMed PubMed Central

25. Singh, P, Gupta, S, Sharma, B. Melatonin receptor and KATP channel modulation in experimental vascular dementia. Physiol Behav 2015;142:66–78. https://doi.org/10.1016/j.physbeh.2015.02.009.Search in Google Scholar PubMed

26. Mohammadi, F, Shakiba, S, Mehrzadi, S, Afshari, K, Rahimnia, AH, Dehpour, AR. Anticonvulsant effect of melatonin through ATP‐sensitive channels in mice. Fund Clin Pharmacol 2019;34:148–55. https://doi.org/10.1111/fcp.12490.Search in Google Scholar PubMed

Received: 2021-09-20
Accepted: 2021-11-03
Published Online: 2021-12-03

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/jbcpp-2021-0289
Keywords for this article
cardioprotection; circadian rhythm; heart rate; physical activity; SUR2A

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Circulating tumor cells in bladder cancer: a new horizon of liquid biopsy for precision medicine
  4. Minireview
  5. PCSK9 and LRP6: potential combination targets to prevent and reduce atherosclerosis
  6. Reviews
  7. The complex relationship between physical activity and diabetes: an overview
  8. Methotrexate related cutaneous adverse drug reactions: a systematic literature review
  9. Long-term use of proton pump inhibitors adversely affects minerals and vitamin metabolism, bone turnover, bone mass, and bone strength
  10. An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics
  11. Original Articles
  12. Apelin-13 protects human neuroblastoma SH-SY5Y cells against amyloid-beta induced neurotoxicity: Involvement of anti oxidant and anti apoptotic properties
  13. Are hypertensive patients with history of coronary artery disease at risk for silent lower extremity artery disease?
  14. The effect of long-term ketogenic diet on serum adiponectin and insulin-like growth factor-1 levels in mice
  15. Increase in cardioprotective SUR2A does not alter heart rate and heart rate regulation by physical activity and diurnal rhythm
  16. Effect of ascorbic acid supplementation on pulmonary functions in healthy adults: a randomized controlled pilot study
  17. Alpha2-antiplasmin deficiency affects depression and anxiety-like behavior and apoptosis induced by stress in mice
  18. Modern gold standard of cardiac output measurement – A simplified bedside measurement of individual oxygen uptake in the cath lab
  19. Electrical vestibular nerve stimulation (VeNS): a follow-up safety assessment of long-term usage
  20. Psychological impact of abnormally invasive placenta: an underestimated and hidden morbidity
  21. Limited diagnostic value of questionnaire-based pre-participation screening algorithms: a “risk-exposed” approach to sports activity
  22. Predictors of abdominal pain severity in patients with constipation-prevalent irritable bowel syndrome
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