Comparative evaluation of infarct-limiting efficiency of postconditioning with lactate in ischemia-reperfusion of the myocardium in young and old rats and rats with transient hypercholesterolemia

Taking into account the high medical and social significance of the problem of treating patients with coronary heart disease and acute myocardial infarction, the search for new effective methods of preventing or weakening ischemic and reperfusion myocardial damage and finding out the mechanisms of their implementation is an urgent task of modern experimental and clinical medicine. The aim of the study was to conduct a comparative analysis and clarification of features of the cardioprotective efficiency of postconditioning with lactate in ischemia-reperfusion of the myocardium in young and old rats and rats with transient hypercholesterolemia (HCE). It was found that remote ischemic postconditioning (RIPostC) in ischemia-reperfusion of the myocardium has an infarction-limiting effect and is accompanied by an increase in the level of lactate in the blood, and lactate after injection into the bloodstream of animals at a dose of 10 mg/kg 25 min after the start of reperfusion leads to a decrease in the size of the necrosis zone in the left ventricular myocardium in young and old rats. However, postconditioning with lactate is not effective in limiting the size of the zone of necrosis in the left ventricular of myocardium in young and old rats with transient HCE. There is reason to suppose that hyperlactatemia takes part in the realization of the cardioprotective effect of RIPostC. The presence of such a risk factor for cardiovascular diseases as HCE can serve as a criterion for excluding the use of postconditioning with lactate as a way to reduce ischemic and reperfusion damage to the myocardium in patients with acute myocardial infarction.

1. Maslov L. N., Tsibul’nikov S. Yu., Tsepokina A. V., Khutornaya M. V., Kutikhin A. G., Gurin A. V., Basalai M. V., Mrochek A. G. Cardioprotrective effect of remote postconditioning: мechanisms and possibilities of clinical application. Klinicheskaya meditsina [Clinical medicine], 2016, vol. 94, no. 9, pp. 650–656 (in Russian).

2. Bautin A. E., Karpova L. I., Marichev A. O., Tashkhanov D. M., Naumenko V. S., Galagudza M. M. Cardioprotective effects of ischemic conditioning: current concepts of mechanisms, experimental evidence, clinical implementation. Translyatsionnaya meditsina [Translational medicine], 2016, vol. 3, no. 1, pp. 50–62 (in Russian).

3. Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre, post, and remote conditioning. Circulation Research, 2015, vol. 116, no. 4, pp. 674–699. https://doi.org/10.1161/CIRCRESAHA.116.305348

4. Donato M., Evelson P., Gelpi R. J. Protecting the heart from ischemia/reperfusion injury: an update on remote ischemic preconditioning and postconditioning. Current Opinion in Cardiology, 2017, vol. 32, no. 6, pp. 784‒790. https://doi.org/10.1097/HCO.0000000000000447

5. Zhao Z.-Q., Corvera J. S., Halcos M. E., Kerendi F., Wang N. P., Guyton R. A., Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. American Journal of Physiology ‒ Heart and Circulatory Physiology, 2003, vol. 285, no. 2, pp. H579–H588. https://doi.org/10.1152/ajpheart.01064.2002

6. Basalay М., Barsukevich V., Mastitskaya S., Mrochek A., Pernow J., Sjöquist P. O., Ackland G. L., Gourine A. V., Gourine A. Remote ischaemic pre- and delayed postconditioning  – similar degree of cardioprotection but distinct mechanisms. Experimental Physiology, 2012, vol. 97, no. 8, pp. 908–917 (in Russian).

7. Cao B., Wang H., Zhang C., Xia M., Yang X. Remote ischemic postconditioning (RIPC) of the upper arm results in protection from cardiac ischemia-reperfusion injury following primary percutaneous coronary intervention (PCI) for acute st-segment elevation myocardial infarction (STEMI). Medical Science Monitor, 2018, vol. 24, pp. 1017–1026. https://doi.org/10.12659/msm.908247

8. Vismont F. I., Chepelev S. N., Yushkevich P. F. Peripheral M-choline-reactive systems in the infarct-limited effect implementation of remote ischemic postconditioning during ischemia-reperfusion of myocardium in experiment. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seryya medytsynskikh navuk = Proceedings of the National Academy of Sciences of Belarus. Medical series, 2019, vol. 16, no. 4, pp. 424–433 (in Russian).

9. Montoya J. J., Fernández N., Monge L., Diéguez G., Villalón A. L. Nitric oxide-mediated relaxation to lactate of coronary circulation in the isolated perfused rat heart. Journal of Cardiosvascular Pharmacology, 2011, vol. 58, no. 4, pp. 392– 398. https://doi.org/10.1097/FJC.0b013e318226bcf7

10. Chepelev S. N., Vismont F. I. Significance of nitrogen monoxide in the implementation of the infarctlimiting effect of remote ischemic postconditioning in myocardial ischemia-reperfusion in young and old rats. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seryya medytsynskikh navuk = Proceedings of the National Academy of Sciences of Belarus. Medical series, 2020, vol. 17, no. 3, pp. 353–364 (in Russian).

11. Groussard C., Morel I., Chevanne M., Monnier M., Cillard J., Delamarche A. Free radical scavenging and antioxidant effects of lactate ion: an in vitro study. Journal of Applied Physiology (1985), 2000, vol. 89, no. 1, pp. 169–175. https://doi.org/10.1152/jappl.2000.89.1.169

12. Trekova N. A., Aksel’rod B. A., Yudichev I. I., Gus’kov D. A., Markin A. V., Popov A. M. Clinical aspects of the dynamics of blood lactate during surgery on the heart and aorta under conditions of cardiopulmonary bypass. Anesteziologiya i reanimatologiya [Anesthesia and resuscitation], 2016, vol. 61, no. 5, pp. 324–329.

13. Brooks G. A. The science and translation of lactate shuttle theory. Cell Metabolism, 2018, vol. 27, no. 4, pp. 757–785. https://doi.org/10.1016/j.cmet.2018.03.008

14. Ritterhoff J., Tian R. Metabolism in cardiomyopathy: every substrate matters. Cardiovascular Research, 2017, vol. 113, no. 4, pp. 411–421. https://doi.org/10.1093/cvr/cvx017

15. Burd L., Jones M., Simmons M., Makowski E. L., Meschia G., Battaglia F. C. Placental production and foetal utilisation of lactate and pyruvate. Nature, 1975, vol. 254, no. 5502, pp. 710–711. https://doi.org/10.1038/254710a0

16. Werner J. C., Sicard R. E. Lactate metabolism of isolated, perfused fetal, and newborn pig hearts. Pediatric Research, 1987, vol. 22, no. 5, pp. 552–556. https://doi.org/10.1203/00006450-198711000-00016

17. Evans R. K., Schwartz D. D., Gladden L. B. Effect of myocardial volume overload and heart failure on lactate transport into isolated cardiac myocytes. Journal of Applied Physiology, 2003, vol. 94, no. 3, pp. 1169–1176. https://doi.org/10.1152/japplphysiol.00778.2002

18. Jopling C., Sleep E., Raya M., Martí M., Raya A., Belmonte J. C. I. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature, 2010, vol. 464, no. 7288, pp. 606–609. https://doi.org/10.1038/nature08899

19. Aguirre A., Montserrat N., Zacchigna S., Nivet E., Hishida T., Krause M. N. [et al.]. In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Cell Stem Cell, 2014, vol. 15, no. 5, pp. 589–604. https://doi.org/10.1016/j.stem.2014.10.003

20. Ordoño J., Pérez-Amodio S., Ball K., Aguirre A., Engel E. Lactate promotes cardiomyocyte dedifferentiation through metabolic reprogramming. bioRxiv, 2020, art. ID 220837392. https://doi.org/10.1101/2020.07.21.213736

21. Zhang J., Huang F., Chen L., Li G., Lei W., Zhao J., Liao Y., Li Y., Li C., Chen M. Sodium lactate accelerates M2 macrophage polarization and improves cardiac function after myocardial infarction in mice. Cardiovascular Therapeutics, 2021, vol. 2021, art. ID 5530541. https://doi.org/10.1155/2021/5530541

22. Bergman B. C., Tsvetkova T., Lowes B., Wolfel E. E. Myocardial glucose and lactate metabolism during rest and atrial pacing in humans. Journal of Physiology, 2009, vol. 587, no. 9, pp. 2087–2099. https://doi.org/10.1113/jphysiol.2008.168286

23. Nalos M., Leverve X. M., Huang S. J., Weisbrodt L., Parkin R., Seppelt I. M., Ting I., Mclean A. S. Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial. Critical Care, 2014, vol. 18, no. 2, p. R48. https://doi.org/10.1186/cc13793

24. Koyama T., Munakata M., Akima T., Kageyama T., Shibata M., Moritani K., Kanki H., Ishikawa S., Mitamura H. Impact of postconditioning with lactate-enriched blood on in-hospital outcomes of patients with ST-segment elevation myocardial infarction. International Journal of Cardiology, 2016, vol. 220, pp. 146–148. https://doi.org/10.1016/j.ijcard.2016.06.176

25. Ruiz-Meana M., Boengler K., Garcia-Dorado D., Hausenloy D. J., Kaambre T., Kararigas G., Perrino C., Schulz R., Ytrehus K. Ageing, sex, and cardioprotection. British Journal of Pharmacology, 2019, vol. 177, no. 23, pp. 5270–5286. https://doi.org/10.1111/bph.14951

26. Andreadou I., Iliodromitis E. K., Lazou A., Görbe A., Giricz Z., Schulz R., Ferdinandy P. Effect of hypercholesterolaemia on myocardial function, ischaemia-reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning. British Journal of Pharmacology, 2017, vol. 174, no. 12, pp. 1555–1569. https://doi.org/10.1111/bph.13704

27. Gizak A., McCubrey J. A., Rakus D. Cell-to-cell lactate shuttle operates in heart and is important in age-related heart failure. Aging, 2020, vol. 12, no. 4, pp. 3388–3406. https://doi.org/10.18632/aging.102818

28. Chepelev S. N., Vismont F. I., Gubkin S. V., Maslov L. N. The influence of old age on cardioprotective efficiency of pharmacological postconditioning using lactic acid in ischemia-reperfusion of the myocardium in experiment. Doklady Natsional’noi akademii nauk Belarusi = Doklady of the National Academy of Sciences of Belarus, 2021, vol. 65, no. 2, pp. 207–216 (in Russian).

29. Li H., Zhou C., Chen D., Fang N., Yao Y., Li L. Failure to protect against myocardial ischemia-reperfusion injury with sevoflurane postconditioning in old rats in vivo. Acta Anaesthesiologica Scandinavica, 2013, vol. 57, no. 8, pp. 1024‒1031. https://doi.org/10.1111/aas.12156

30. Jiang J. J., Li C., Li H., Zhang L., Lin Z. H., Fu B. J., Zeng Y. M. Sevoflurane postconditioning affects post-ischaemic myocardial mitochondrial ATP-sensitive potassium channel function and apoptosis in ageing rats. Clinical and Experimental Pharmacology and Physiology, 2016, vol. 43, no. 5, pp. 552–561. https://doi.org/10.1111/1440-1681

31. Ferdinandy P., Schulz R., Baxter G. F. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning and postconditioning. Pharmacological Reviews, 2007, vol. 59, no. 4, pp. 418–458. https://doi.org/10.1124/pr.107.06002

32. Wilson S. H., Simari R. D., Best P. J. M., Peterson T. E., Lerman L. O., Aviram M., Nath K. A., HolmesJr D. R., Lerman A. Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering. Arteriosclerosis, Thrombosis, and Vascular Biology, 2001, vol. 21, no. 1, pp. 122–128. https://doi.org/10.1161/01.atv.21.1.122

33. Osipov R. M., Bianchi C., Feng J., Clements R. T., Liu Y., Robich M. P., Glazer H. P., Sodha N. R., Sellke F. W. Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion. Circulation, 2009, vol. 120, no. 11S, pp. S22–S30. https://doi.org/10.1161/CIRCULATIONAHA.108.842724

34. Wu N., Zhang X., Guan Y., Shu W., Jia P., Jia D. Hypercholesterolemia abrogates the cardioprotection of ischemic postconditioning in isolated rat heart: roles of glycogen synthase kinase-3β and the mitochondrial permeability transition pore. Cell Biochemistry and Biophysics, 2014, vol. 69, no. 1, pp. 123–130. https://doi.org/10.1007/s12013-013-9778-2

35. Zhao H., Wang Y., Wu Y., Li X., Yang G., Ma X., Zhao R., Liu H. Hyperlipidemia does not prevent the cardioprotection by postconditioning against myocardial ischemia/reperfusion injury and the involvement of hypoxia inducible factor-1 alpha upregulation. Acta Biochimica et Biophysica Sinica, 2009, vol. 41, no. 9, pp. 745–753. https://doi.org/10.1093/abbs/gmp063

36. Tang X.-L., Sato H., Tiwari S., Dawn B., Bi Q., Li Q., Shirk G., Bolli R. Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min. American Journal of Physiology Heart and Circulatory Physiology, 2006, vol. 291, no. 5, pp. H2308–H2317. https://doi.org/10.1152/ajpheart.00479.2006

37. Fishbein M. C., Meerbaum S., Rit J., Lando U., Kanmatsuse K., Mercier J. C., Corday E., Ganz W. Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. American Heart Journal, 1981, vol. 101, no. 5, pp. 593–600. https://doi.org/10.1016/0002-8703(81)90226-x

38. Chepelev S. N., Vismont F. I., Gubkin S. V., Maslov L. N. Cardioprotective efficiency of pharmacological postconditioning using lactic acid in ischemia-reperfusion of the myocardium in rats with transitional hypercholesterolemia. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seryya medytsynskikh navuk = Proceedings of the National Academy of Sciences of Belarus. Medical series, 2021, vol. 18, no. 2, pp. 135–146 (in Russian).

39. Chepelev S. N., Vismont F. I., Gubkin S. V. On the significance of hyperlactatemia in the implementation of the infarct-limiting effect of remote ischemic postconditioning in myocardial ischemia-reperfusion in the experiment. Doklady Natsional’noi akademii nauk Belarusi = Doklady of the National Academy of Sciences of Belarus, 2020, vol. 64, no. 3, pp. 332‒340 (in Russian).

40. Sack M., Murphy E. The role of comorbidities in cardioprotection. Journal of Cardiovascular Pharmacology and Therapeutics, 2011, vol. 16, no. 3–4, pp. 267–272. https://doi.org/10.1177/1074248411408313