The apelinergic system as an alternative to catecholamines in low-output septic shock

David Coquerel, Xavier Sainsily, Lauralyne Dumont, Philippe Sarret, Éric Marsault, Mannix Auger-Messier, Olivier Lesur, David Coquerel, Xavier Sainsily, Lauralyne Dumont, Philippe Sarret, Éric Marsault, Mannix Auger-Messier, Olivier Lesur

Abstract

Catecholamines, in concert with fluid resuscitation, have long been recommended in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has emerged, trending toward decatecholaminization. Contextually, it is time to re-examine the "maintaining blood pressure" paradigm by identifying safer and life-saving alternatives. We put in perspective the emerging and growing knowledge on a promising alternative avenue: the apelinergic system. This target exhibits invaluable pleiotropic properties, including inodilator activity, cardio-renal protection, and control of fluid homeostasis. Taken together, its effects are expected to be greatly beneficial for patients in septic shock.

Keywords: Apelin (APJ) receptor; Apelinergic system; Biased signaling; Decatecholaminization; Inodilator; Septic shock.

Figures

Fig. 1
Fig. 1
Potential impacts of modulating the apelinergic system in human septic shock with multi-organ failure (MOF). Acute and continuous infusions of the endogenous apelin receptor (APJ) ligands Apelin-13 (APLN-13) and Eleabela (ELA) display several beneficial effects in preclinical septic shock (i.e., endotoxin and cecal ligation and puncture models) as well as in sepsis-related organ failure. Both APLN-13 and ELA reduce bloodstream and tissue inflammation, improve cardiovascular hemodynamics (e.g., enhanced inotropy, reduced pre- and after-load, as well as vascular permeability) and enhance diuresis. Specifically, APLN-13 and ELA exhibit a differential interplay with the vasopressinergic system and therefore modulate fluid homeostasis. APLN-13 alleviates pituitary AVP release, thus inducing low blood AVP and enhanced aquaresis. In contrast, ELA stimulates diuresis in a pressure- and kidney-dependent manner without modified blood AVP, preserving functional water reabsorption and contributing to enhanced plasma volume. Both APLN-13 and ELA infusions confer tissue protection and contribute to reduced mortality and improved outcomes in experimental septic shock. Inhibition of platelet function has been recently described as a novel property of APLN-13, potentially relevant to septic shock, but not addressed in this perspective. CNS central nervous system
Fig. 2
Fig. 2
Hemodynamic drug support in septic shock-related myocardial dysfunction: pharmacological state-of-the-art evidence and new approach concepts. Current recommendations after optimal fluid resuscitation are the introduction of adrenergic agonists with emphasis on the β1AR agonist dobutamine when cardiac index remains low, and somewhat often a hyporesponsiveness/increased dosage profile along with β1AR myocardial down-regulation. In spite of this decreased AR availability, cardioprotection and improved survival have been obtained with β1AR blockade. Apelinergic agonists offer cardio-protection and improved outcomes with a high responsiveness/dosage profile at the pre-clinical side. References supporting assumptions are cited in the text. ELA Eleabela
Fig. 3
Fig. 3
The concept of biased signaling. a) In the classic model, ligand L1 binds and elicits a set of signaling pathways leading indiscriminately to multiple physiological effects. b) In biased signaling, ligand L2 biases the receptor toward signaling pathway 1, whereas ligand L3 induces bias for pathway 2, leading to distinct physiological outcomes

References

    1. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17:407–20. doi: 10.1038/nri.2017.36.
    1. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63–78. doi: 10.1016/S0140-6736(04)17667-8.
    1. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41:1167–74. doi: 10.1097/CCM.0b013e31827c09f8.
    1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45:486–552. doi: 10.1097/CCM.0000000000002255.
    1. Vieillard-Baron A, Caille V, Charron C, Belliard G, Page B, Jardin F. Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med. 2008;36:1701–6. doi: 10.1097/CCM.0b013e318174db05.
    1. Kumar A, Schupp E, Bunnell E, Ali A, Milcarek B, Parrillo JE. Cardiovascular response to dobutamine stress predicts outcome in severe sepsis and septic shock. Crit Care. 2008;12:R35. doi: 10.1186/cc6814.
    1. Cariou A, Pinsky MR, Monchi M, Laurent I, Vinsonneau C, Chiche JD, et al. Is myocardial adrenergic responsiveness depressed in human septic shock? Intensive Care Med. 2008;34:917–22. doi: 10.1007/s00134-008-1022-y.
    1. McNally EM. Can we do better than dobutamine? Circ Res. 2013;113:355–7. doi: 10.1161/CIRCRESAHA.113.302000.
    1. Galanth C, Hus-Citharel A, Li B, Llorens-Cortes C. Apelin in the control of body fluid homeostasis and cardiovascular functions. Curr Pharm Des. 2012;18:789–98. doi: 10.2174/138161212799277770.
    1. Bertrand C, Valet P, Castan-Laurell I. Apelin and energy metabolism. Front Physiol. 2015;6:115. doi: 10.3389/fphys.2015.00115.
    1. Adam F, Khatib AM, Lopez JJ, Vatier C, Turpin S, Muscat A, et al. Apelin: an antithrombotic factor that inhibits platelet function. Blood. 2016;127:908–20. doi: 10.1182/blood-2014-05-578781.
    1. Coquerel D, Chagnon F, Sainsily X, Dumont L, Murza A, Cote J, et al. ELABELA improves cardio-renal outcome in fatal experimental septic shock. Crit Care Med. 2017;45:e1139–48. doi: 10.1097/CCM.0000000000002639.
    1. Schmittinger CA, Torgersen C, Luckner G, Schroder DC, Lorenz I, Dunser MW. Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. Intensive Care Med. 2012;38:950–8. doi: 10.1007/s00134-012-2531-2.
    1. Hartmann C, Radermacher P, Wepler M, Nubaum B. Non-hemodynamic effects of catecholamines. Shock. 2017;40:390–400. doi: 10.1097/SHK.0000000000000879.
    1. de Montmollin E, Aboab J, Mansart A, Annane D. Bench-to-bedside review: Beta-adrenergic modulation in sepsis. Crit Care. 2009;13:230. doi: 10.1186/cc8026.
    1. Silverman HJ, Penaranda R, Orens JB, Lee NH. Impaired beta-adrenergic receptor stimulation of cyclic adenosine monophosphate in human septic shock: association with myocardial hyporesponsiveness to catecholamines. Crit Care Med. 1993;21:31–9. doi: 10.1097/00003246-199301000-00010.
    1. Macarthur H, Westfall TC, Riley DP, Misko TP, Salvemini D. Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci U S A. 2000;97:9753–8. doi: 10.1073/pnas.97.17.9753.
    1. Auchet T, Regnier MA, Girerd N, Levy B. Outcome of patients with septic shock and high-dose vasopressor therapy. Ann Intensive Care. 2017;7:43. doi: 10.1186/s13613-017-0261-x.
    1. Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock a randomized clinical trial. JAMA. 2013;310:1683–91. doi: 10.1001/jama.2013.278477.
    1. Kimmoun A, Louis H, Al Kattani N, Delemazure J, Dessales N, Wei C, et al. beta1-Adrenergic inhibition improves cardiac and vascular function in experimental septic shock. Crit Care Med. 2015;43:e332–40. doi: 10.1097/CCM.0000000000001078.
    1. Asfar P, Russell JA, Tuckermann J, Radermacher P. Selepressin in septic shock: a step toward decatecholaminization? Crit Care Med. 2016;44:234–6. doi: 10.1097/CCM.0000000000001441.
    1. Rudiger A. Beta-block the septic heart. Crit Care Med. 2010;3(Suppl):S608–12. doi: 10.1097/CCM.0b013e3181f204ca.
    1. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–87. doi: 10.1056/NEJMoa067373.
    1. He X, Su F, Taccone FS, Laporte R, Kjolbye AL, Zhang J, et al. A selective V(1A) receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock. Crit Care Med. 2016;44:23–31. doi: 10.1097/CCM.0000000000001380.
    1. Russell JA, Vincent JL, Kjolbye AL, Olsson H, Blemings A, Spapen H, et al. Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. Crit Care. 2017;21:213. doi: 10.1186/s13054-017-1798-7.
    1. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377:419–30. doi: 10.1056/NEJMoa1704154.
    1. O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene. 1993;136(1–2):355–60. doi: 10.1016/0378-1119(93)90495-O.
    1. Habata Y, Fujii R, Hosoya M, Fukusumi S, Kawamata Y, Hinuma S, et al. Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochim Biophys Acta. 1999;1452(1):25–35. doi: 10.1016/S0167-4889(99)00114-7.
    1. Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, et al. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem. 2000;275:21061–7. doi: 10.1074/jbc.M908417199.
    1. Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension 2009;54:598–604.
    1. Zhen EY, Higgs RE, Gutierrez JA. Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma. Anal Biochem. 2013;442:1–9. doi: 10.1016/j.ab.2013.07.006.
    1. Perjes A, Skoumal R, Tenhunen O, Konyi A, Simon M, Horvath IG, et al. Apelin increases cardiac contractility via protein kinase Cepsilon- and extracellular signal-regulated kinase-dependent mechanisms. PLoS One. 2014;9:e93473. doi: 10.1371/journal.pone.0093473.
    1. Wang C, Du JF, Wu F, Wang HC. Apelin decreases the SR Ca2+ content but enhances the amplitude of [Ca2+]i transient and contractions during twitches in isolated rat cardiac myocytes. Am J Physiol Heart Circ Physiol. 2008;294:H2540–6. doi: 10.1152/ajpheart.00046.2008.
    1. Chamberland C, Barajas-Martinez H, Haufe V, Fecteau MH, Delabre JF, Burashnikov A, et al. Modulation of canine cardiac sodium current by Apelin. J Mol Cell Cardiol. 2010;48:694–701. doi: 10.1016/j.yjmcc.2009.12.011.
    1. Szokodi I, Tavi P, Foldes G, Voutilainen-Myllyla S, Ilves M, Tokola H, et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res. 2002;91:434–40. doi: 10.1161/01.RES.0000033522.37861.69.
    1. Ashley EA, Powers J, Chen M, Kundu R, Finsterbach T, Caffarelli A, et al. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc Res. 2005;65:73–82. doi: 10.1016/j.cardiores.2004.08.018.
    1. Japp AG, Cruden NL, Amer DA, Li VK, Goudie EB, Johnston NR, et al. Vascular effects of apelin in vivo in man. J Am Coll Cardiol. 2008;52:908–13. doi: 10.1016/j.jacc.2008.06.013.
    1. Murza A, Sainsily X, Coquerel D, Cote J, Marx P, Besserer-Offroy E, et al. Discovery and structure-activity relationship of a bioactive fragment of ELABELA that modulates vascular and cardiac functions. J Med Chem. 2016;59:2962–72. doi: 10.1021/acs.jmedchem.5b01549.
    1. Chng SC, Ho L, Tian J, Reversade B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013;27:672–80. doi: 10.1016/j.devcel.2013.11.002.
    1. Ho L, Tan SY, Wee S, Wu Y, Tan SJ, Ramakrishna NB, et al. ELABELA is an endogenous growth factor that sustains hESC self-renewal via the PI3K/AKT pathway. Cell Stem Cell. 2015;17:435–47. doi: 10.1016/j.stem.2015.08.010.
    1. Perjes A, Kilpio T, Ulvila J, Magga J, Alakoski T, Szabo Z, et al. Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart. Basic Res Cardiol. 2016;111:2. doi: 10.1007/s00395-015-0521-6.
    1. Yang P, Read C, Kuc RE, Buonincontri G, Southwood M, Torella R, et al. Elabela/Toddler is an endogenous agonist of the Apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension. Circulation. 2017;135:1160–73. doi: 10.1161/CIRCULATIONAHA.116.023218.
    1. Ho L, van Dijk M, Chye STJ, Messerschmidt DM, Chng SC, Ong S, et al. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science. 2017;357:707–13. doi: 10.1126/science.aam6607.
    1. Sato T, Sato C, Kadowaki A, Watanabe H, Ho L, Ishida J, et al. ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage. Cardiovasc Res. 2017;113:760–9. doi: 10.1093/cvr/cvx061.
    1. Chagnon F, Coquerel D, Salvail D, Marsault E, Dumaine R, Auger-Messier M, et al. Apelin compared with dobutamine exerts cardioprotection and extends survival in a rat model of endotoxin-induced myocardial dysfunction. Crit Care Med. 2016;45:e391–8. doi: 10.1097/CCM.0000000000002097.
    1. Luo K, Long H, Xu B, Luo Y. Apelin attenuates postburn sepsis via a phosphatidylinositol 3-kinase/protein kinase B dependent mechanism: a randomized animal study. Int J Surg. 2015;21:22–7. doi: 10.1016/j.ijsu.2015.06.072.
    1. Lesur O, Roussy JF, Chagnon F, Gallo-Payet N, Dumaine R, Sarret P, et al. Proven infection-related sepsis induces a differential stress response early after ICU admission. Crit Care. 2010;14:R131. doi: 10.1186/cc9102.
    1. De Mota N, Reaux-Le Goazigo A, El Messari S, Chartrel N, Roesch D, Dujardin C, et al. Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc Natl Acad Sci U S A. 2004;101:10464–9. doi: 10.1073/pnas.0403518101.
    1. Roberts EM, Newson MJ, Pope GR, Landgraf R, Lolait SJ, O'Carroll AM. Abnormal fluid homeostasis in apelin receptor knockout mice. J Endocrinol. 2009;202:453–62. doi: 10.1677/JOE-09-0134.
    1. Hus-Citharel A, Bodineau L, Frugiere A, Joubert F, Bouby N, Llorens-Cortes C. Apelin counteracts vasopressin-induced water reabsorption via cross talk between apelin and vasopressin receptor signaling pathways in the rat collecting duct. Endocrinology. 2014;155:4483–93. doi: 10.1210/en.2014-1257.
    1. Russell JA, Walley KR. Vasopressin and its immune effects in septic shock. J Innate Immun. 2010;2:446–60. doi: 10.1159/000318531.
    1. Russell JA, Fjell C, Hsu JL, Lee T, Boyd J, Thair S, et al. Vasopressin compared with norepinephrine augments the decline of plasma cytokine levels in septic shock. Am J Respir Crit Care Med. 2013;188:356–64. doi: 10.1164/rccm.201302-0355OC.
    1. Pupo AS, Duarte DA, Lima V, Teixeira LB, Parreiras ESLT, Costa-Neto CM. Recent updates on GPCR biased agonism. Pharmacol Res. 2016;112:49–57. doi: 10.1016/j.phrs.2016.01.031.
    1. Audet M, Bouvier M. Restructuring G-protein-coupled receptor activation. Cell. 2012;151:14–23. doi: 10.1016/j.cell.2012.09.003.
    1. Brame AL, Maguire JJ, Yang P, Dyson A, Torella R, Cheriyan J, et al. Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension. 2015;65:834–40. doi: 10.1161/HYPERTENSIONAHA.114.05099.
    1. Gurevich VV, Gurevich EV. Overview of different mechanisms of arrestin-mediated signaling. Curr Protocols Pharmacol 2014;67:Unit 2 10 11–19.
    1. Fan H, Bitto A, Zingarelli B, Luttrell LM, Borg K, Halushka PV, et al. Beta-arrestin 2 negatively regulates sepsis-induced inflammation. Immunology. 2010;130:344–51. doi: 10.1111/j.1365-2567.2009.03185.x.
    1. Yan H, Li H, Denney J, Daniels C, Singh K, Chua B, et al. Beta-arrestin 2 attenuates cardiac dysfunction in polymicrobial sepsis through gp130 and p38. Biochem Biophys Rep. 2016;7:130–7.

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