Peptides – cardioprotective drugs of the future. Intermedin

Despite the undoubted successes achieved in the treatment of acute myocardial infarction (AMI), the problem of increasing the effectiveness of treating this disease remains relevant. Despite the undoubted successes achieved in the treatment of AMI, the problem of increasing the effectiveness of treating this disease remains relevant. With the introduction of percutaneous coronary intervention into clinical practice, myocardial reperfusion injury comes to the fore, for which drugs used to treat AMI are of little effectiveness. In our opinion, polypeptides, particularly intermedin (adrenomedullin-2), may prove to be more effective drugs for preventing myocardial reperfusion injury. Analysis of the data presented in the article indicates that this polypeptide can prevent myocardial reperfusion injury and enhance the tolerance of isolated cardiomyocytes to hypoxia/reoxygenation. It has been shown that the cardioprotective and cytoprotective effect of intermedin is associated with the activation of the RAMP2 receptor and the stimulation of several kinases. The cardioprotective effect depends on the inhibition of cardiomyocyte apoptosis and the stimulation of cardiomyocyte autophagy. The article demonstrates the expediency of conducting preclinical studies of the infarct-limiting effect of enzyme-resistant analogs of intermedin in animals with coronary occlusion and reperfusion.

Aim: To assess published data on the cardioprotective effect of intermedin. Literature search was carried out in the PubMed and eLibrary databases using the queries "intermedin", "cardioprotective effect of intermedin", "adrenomedullin-2", "myocardial ischemia reperfusion", "cardiomyocytes hypoxia reoxygenation". The search was conducted without strict time limitations, with an emphasis on experimental and review works dedicated to the cardioprotective effects of intermedin. The review includes the most relevant studies (48 sources).

1. Currey E.M., Falconer N., Isoardi K.Z., Barras M. Impact of pharmacists during in-hospital resuscitation or medical emergency response events: A systematic review. Am. J. Emerg. Med. 2024;75:98–110. DOI: 10.1016/j.ajem.2023.10.020 EDN: NPMEYD

2. Ashraf S., Farooq U., Shahbaz A., et al. Factors Responsible for Worse Outcomes in STEMI Patients with Early vs Delayed Treatment Presenting in a Tertiary Care Center in a Third World Country. Curr. Probl. Cardiol. 2024;49(1):102049. DOI: 10.1016/j.cpcardiol.2023.102049 EDN: NOJLBM

3. Nanavaty D., Sinha R., Kaul D., et al. Impact of COVID-19 on Acute Myocardial Infarction: A National Inpatient Sample Analysis. Curr. Probl. Cardiol. 2024;49(1):102030. DOI: 10.1016/j.cpcardiol.2023.102030 EDN: TFNRTO

4. Hti Lar Seng N.S., Zeratsion G., Pena Zapata O.Y., et al. Utility of Cardiac Troponins in Patients with Chronic Kidney Disease. Cardiol. Rev. 2024;32(1):62-70. DOI: 10.1097/CRD.0000000000000461 EDN: FCORCT

5. Luo Q., Sun W., Li Z., et al. Biomaterials-mediated targeted therapeutics of myocardial ischemia-reperfusion injury. Biomaterials. 2023;303:122368. DOI: 10.1016/j.biomaterials.2023.122368 EDN: IDLSVE

6. Motova A.V., Karetnikova V.N., Osokina A.V., et al. Type 2 myocardial infarction: Diagnostic features in real clinical practice. Siberian Journal of Clinical and Experimental Medicine. 2022;37(3):75–82. (In Russ.). DOI: 10.29001/2073-8552-2022-37-3-75-82 EDN: LFHJYB

7. Vyshlov E.V., Alexeeva Ya.A., Ussov W.Yu., et al. Phenomena of microvascular myocardial injury in patients with primary ST-segment elevation myocardial infarction: Prevalence and association with clinical characteristics. Siberian Journal of Clinical and Experimental Medicine. 2022;37(1):36–46. DOI: 10.29001/2073-8552-2021-36-4-36-46 EDN: LOLFFW

8. Panteleev O.O., Ryabov V.V. Cardiogenic shock: What's new? Siberian Journal of Clinical and Experimental Medicine. 2021;36(4):45–51. (In Russ.). DOI: 10.29001/2073-8552-2021-36-4-45-51 EDN: TGEJXO

9. Li M., Hu L., Li L. Research progress of intra-aortic balloon counterpulsation in the treatment of acute myocardial infarction with cardiogenic shock: A review. Medicine (Baltimore). 2023;102(49):e36500. DOI: 10.1097/MD.0000000000036500 EDN: TFIQTX

10. McCartney P.J., Berry C. Redefining successful primary PCI. Eur. Heart J. Cardiovasc. Imaging. 2019;20(2):133–135. DOI: 10.1093/ehjci/jey159 EDN: WVYQDL

11. Maslov L.N., Popov S.V., Mukhomedzyanov A.V., et al. Reperfusion Cardiac Injury: Receptors and the Signaling Mechanisms. Curr. Cardiol. Rev. 2022;18(5):63–79. DOI: 10.2174/1573403X18666220413121730 EDN: JMTGVG

12. Roh J., Chang C.L., Bhalla A., et al. Intermedin Is a Calcitonin/Calcitonin Gene-related Peptide Family Peptide Acting through the Calcitonin Receptor-like Receptor/Receptor Activity-modifying Protein Receptor Complexes. J. Biolog. Chem. 2004;279(8):7264–7274. DOI: 10.1074/jbc.M305332200

13. Takei Y., Inoue K., Ogoshi M., et al. Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator. FEBS Lett. 2004;556(1-3):53–58. DOI: 10.1016/S0014-5793(03)01368-1 EDN: EU-RRGD

14. Chang C.L., Roh J., Hsu S.Y.T. Intermedin, a novel calcitonin family peptide that exists in teleosts as well as in mammals: A comparison with other calcitonin/intermedin family peptides in vertebrates. Peptides (N.Y.). 2004;25(10):1633–1642. DOI: 10.1016/j.peptides.2004.05.021

15. Yang J.H., Jia Y.X., Pan C.S., et al. Effects of intermedin1-53 on cardiac function and ischemia/reperfusion injury in isolated rat hearts. Biochem. Biophys. Res. Commun. 2005;327(3):713–719. DOI: 10.1016/j.bbrc.2004.12.071

16. Zhang S., Xu M., Wang X. Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases. Br. J. Pharmacol. 2018;175(8):1230–1240. DOI: 10.1111/bph.13814 EDN: YCYQAP

17. Morimoto R., Satoh F., Murakami O., et al. Expression of adrenomedullin2/intermedin in human brain, heart, and kidney. Peptides (N.Y.). 2007;28(5):1095–1103. DOI: 10.1016/j.peptides.2007.01.018

18. Takahashi K., Kikuchi K., Maruyama Y., et al. Immunocytochemical localization of adrenomedullin 2/intermedin-like immunoreactivity in human hypothalamus, heart and kidney. Peptides (N.Y.). 2006;27(6):1383– 1389. DOI: 10.1016/j.peptides.2005.11.004

19. Naot D., Musson D.S., Cornish J. The Activity of Peptides of the Calcitonin Family in Bone. Physiol. Rev. 2019;99(1):781–805. DOI: 10.1152/physrev.00066.2017

20. de Miranda D.C., de Oliveira Faria G., Hermidorff M.M., et al. Pre- and Post-Conditioning of the Heart: An Overview of Cardioprotective Signaling Pathways. Curr. Vasc. Pharmacol. 2021;19(5):499–524. DOI: 10.2174/1570161119666201120160619 EDN: WOOCBL

21. Bell D., Campbell M., Ferguson M., et al. AM 1 -receptor-dependent protection by intermedin of human vascular and cardiac non-vascular cells from ischaemia-reperfusion injury. J. Physiol. 2012;590(5):1181–1197. DOI: 10.1113/jphysiol.2011.221895 EDN: UALXTB

22. Bell D., Campbell M., McAleer S.F., et al. Endothelium-derived intermedin/adrenomedullin-2 protects human ventricular cardiomyocytes from ischaemia-reoxygenation injury predominantly via the AM 1 receptor. Peptides (N.Y.). 2016;76:1–13. DOI: 10.1016/j.peptides.2015.12.005

23. Qin Y.W., Teng X., He J.Q., et al. Increased plasma levels of intermedin and brain natriuretic peptide associated with severity of coronary stenosis in acute coronary syndrome. Peptides (N.Y.). 2013;42:84–88. DOI: 10.1016/j.peptides.2013.01.011

24. Lv Z., Wu K., Chen X., et al. Plasma intermedin levels in patients with acute myocardial infarction. Peptides (N.Y.). 2013;43:121–125. DOI: 10.1016/j.peptides.2013.03.007

25. Tang B., Zhong Z., Shen H.W., et al. Intermedin as a prognostic factor for major adverse cardiovascular events in patients with ST-segment elevation acute myocardial infarction. Peptides (N.Y.). 2014;58:98–102. DOI: 10.1016/j.peptides.2014.06.009

26. Bell D., Gordon B.J., Lavery A., et al. Plasma levels of intermedin (adrenomedullin-2) in healthy human volunteers and patients with heart failure. Peptides (N.Y.). 2016;76:19–29. DOI: 10.1016/j.peptides.2015.12.003

27. Li P., Shi L., Han Y., et al. Prognostic Value of Plasma Intermedin Level in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome. Medicine. 2016;95(16):e3422. DOI: 10.1097/MD.0000000000003422

28. Zhang H., Jiang W., Liu J.Y., et al. Intermedin is upregulated and has protective roles in a mouse ischemia/reperfusion model. Hyperten. Res. 2009;32(10):861–868. DOI: 10.1038/hr.2009.120

29. Li H., Bian Y., Zhang N., et al. Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats. Cardiovasc. Diabetol. 2013;12(1):91. DOI: 10.1186/1475-2840-12-91 EDN: RIVCJH

30. Yang S.M., Liu J., Li C.X. Intermedin protects against myocardial ischemia-reperfusion injury in hyperlipidemia rats. Genet. Mol. Res. 2014;13(4):8309–8319. DOI: 10.4238/2014.October.20.7

31. Teng X., Bian Y., Cai Y., et al. Downregulation of Endogenous Intermedin Augmented Myocardial Injury in Rats with Ischemia/Reperfusion. Hormone and Metabolic Research. 2013;45(3):206–212. DOI: 10.1055/s-0032-1327572

32. Song J.Q., Teng X., Cai Y., et al. Activation of Akt/GSK-3β signaling pathway is involved in intermedin1-53 protection against myocardial apoptosis induced by ischemia/reperfusion. Apoptosis. 2009;14(9):1061–1069. DOI: 10.1007/s10495-009-0382-2 EDN: AZFCNF

33. Zhao L., Peng D.Q., Zhang J., et al. Extracellular signal-regulated kinase 1/2 activation is involved in intermedin1-53 attenuating myocardial oxidative stress injury induced by ischemia/reperfusion. Peptides (N.Y.). 2012;33(2):329–335. DOI: 10.1016/j.peptides.2011.12.016 EDN: XZHMVN

34. Wei P., Yang X.J., Fu Q., et al. Intermedin attenuates myocardial infarction through activation of autophagy in a rat model of ischemic heart failure via both cAMP and MAPK/ERK1/2 pathways. Int. J. Clin. Exp. Pathol. 2015;8(9):9836–44. EDN: YZZXMP

35. Popov S.V., Mukhomedzyanov A.V., Voronkov N.S., et al. Regulation of autophagy of the heart in ischemia and reperfusion. Apoptosis. 2023;28(1–2):55–80. DOI: 10.1007/s10495-022-01786-1 EDN: HCBZOI

36. Liao H., Wang Z., Zhang X., et al. Intermedin induces autophagy and attenuates hypoxia-induced injury in cardiomyocytes by regulation of MALAT1/ULK1. Peptides (N.Y.). 2023;160:170917. DOI: 10.1016/j.peptides.2022.170917 EDN: JUJBCI

37. Qiao X., Wang L., Wang Y., et al. Intermedin attenuates renal fibrosis by induction of heme oxygenase-1 in rats with unilateral ureteral obstruction. BMC Nephrol. 2017;18(1):232. DOI: 10.1186/s12882-017-0659-6 EDN: ARCXBP

38. Smith R.S., Gao L., Bledsoe G., et al. Intermedin is a new angiogenic growth factor. Am. J. Physiol. Heart Circ. Physiol. 2009;297(3):H1040– H1047. DOI: 10.1152/ajpheart.00404.2009

39. Jolly L., March J., Kemp P., et al. Mechanisms involved in the regional haemodynamic effects of intermedin (adrenomedullin 2) compared with adrenomedullin in conscious rats. Br. J. Pharmacol. 2009;157(8):1502-1513. DOI: 10.1111/j.1476-5381.2009.00306.x

40. Dong F., Taylor M.M., Samson W.K., Ren J. Intermedin (adrenomedullin-2) enhances cardiac contractile function via a protein kinase C- and protein kinase A-dependent pathway in murine ventricular myocytes. J. Appl. Physiol. 2006;101(3):778–784. DOI: 10.1152/japplphysi-ol.01631.2005

41. Kandilci H.B., Gumusel B., Lippton H. Intermedin/adrenomedullin-2 (IMD/AM2) relaxes rat main pulmonary arterial rings via cGMP-dependent pathway: Role of nitric oxide and large conductance calcium-activated potassium channels (BKCa). Peptides (N.Y.). 2008;29(8):1321– 1328. DOI: 10.1016/j.peptides.2008.04.008

42. Gong Y.S., Fan X.F., Wu X.M., et al. Changes of intermedin/adreno-medullin 2 and its receptors in the right ventricle of rats with chronic hypoxic pulmonary hypertension. Sheng Li Xue Bao. 2007;59(2):210–214. PMID: 17437045

43. Naryzhnaya N.V., Maslov L.N., Derkachev I.A., et al. The effect of an adaptation to hypoxia on cardiac tolerance to ischemia/reperfusion. J. Biomed. Res. 2022;37(4):230–254. DOI: 10.7555/JBR.36.20220125 EDN: VNFGOD

44. Burtscher J., Citherlet T., Camacho-Cardenosa A., et al. Mechanisms underlying the health benefits of intermittent hypoxia conditioning. J. Physiol. 2023. DOI: 10.1113/JP285230 EDN: JIQKRX

45. Rybnikova E., Lukyanova L. Molecular Mechanisms of Adaptation to Hypoxia. Int. J. Mol. Sci. 2023;24(5):4563. DOI: 10.3390/ijms24054563 EDN: MMAECI

46. Maslov L.N., Popov S.V., Naryzhnaya N.V., et al. The regulation of necroptosis and perspectives for the development of new drugs preventing ischemic/reperfusion of cardiac injury. Apoptosis. 2022;27 (9–10):697–719. DOI: 10.1007/s10495-022-01760-x EDN: EGRPIZ

47. Naryzhnaya N.V., Maslov L.N., Popov S.V., et al. Pyroptosis is a drug target for prevention of adverse cardiac remodeling: The crosstalk between pyroptosis, apoptosis, and autophagy. J. Biomed. Res. 2022;36(6):375–389. DOI: 10.7555/JBR.36.20220123 EDN: RKIQLP

48. Fang X., Ardehali H., Min J., Wang F. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat. Rev. Cardiol. 2023;20(1):7–23. DOI: 10.1038/s41569-022-00735-4 EDN: SYWGJH