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Volume 3 Supplement 1

ESICM LIVES 2015

Myocardial impact and cardioprotective effects of apelin-13 and a c-terminal-modified analog during lps and clp experimental sepsis

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Introduction

Apelin-13 (APL-13) is a member of an endogenous peptide's family (APLs) with powerful inotropic and cardioprotective properties. APLs bind to the dedicated receptor APJ-R, a member of the G protein-coupled receptor superfamily, all being widely expressed in the cardiovascular system. We have already shown that APL-13 infusion, was protective against LPS-induced myocardial dysfunction and death vs. dobutamine [1]. Furthermore, we have shown that, C-terminal Phe(13) modification of APL-13 by unnatural amino acids can change ligand binding and APJ-R signaling [2].

Objectives

Understanding the beneficial impact of APL-13 on LPS-induced myocardial injury vs. dobutamine, and assessing functional and biological effects of a new selected linear APL-13 analog with enhanced affinity, and their impact in the context of sepsis.

Methods

Myocardial dysfunction was induced by intra-peritoneal injection of LPS (E. Coli 055:B5, 10 mg/kg) or Cecal Ligature and Puncture (CLP) in male Sprague-Dawley rats. Myocardial injury was biologically evaluated by analyzing of different cellular pathway of apoptosis and inflammation by Western blot. Myocardial function was assessed ex-vivo by Langendorff and in vivo by echocardiography by comparing APL-13 to Tyr(Obn). Tyr(OBn)(13) substitution led to a 60-fold increase in binding affinity vs. APL-13 [2].

Results

LPS-challenged rats treated with APL-13 exhibited a clear reduction of both apoptosis (cleaved caspase-3, BAX/BCL-2 ratio) and inflammation (iNOS and MIF) markers, with significant alterations in the Akt/GSK3b/mTor and P38/Erk pathways underscoring the cardioprotective effect of APLs. Organic Langendorff assays confirmed cellular data [2] in that enhanced affinity confers to Tyr(Obn) analog a more effective and potent inotropic activity than APL-13, as shown by the increased left ventricular developed pressure (LVDP) (% baseline, 1pM : APL-13, 8 ± 13 vs. Tyr(Obn), 60 ± 15 ; p < 0.05), (30pM : APL-13, 124 ± 25 vs. Tyr(Obn), 372 ± 106 ; p < 0.05). APLs sensibility was increased in 8h CLP-challenged hearts, as it was in 24h LPS-challenged hearts [1], suggesting upregulation of the myocardial apelinergic pathway during polymicrobial sepsis. Indeed, CLP model of sepsis was characterized at 8h by a reduced cardiac output (Sham, 170 ± 3 vs. CLP, 99 ± 5 ml/min, p < 0.05) with an increased parietal thickness (Sham, 0.15 ± 0.002 vs. CLP, 0.23 ± 0.003 cm, p < 0.05) in vivo.

Conclusions

APLs are new safer supporting drugs in sepsis. Chemical modifications can optimize the inotropic potency of APLs opening a novel field of therapeutic opportunities. Ongoing works are to evaluate the functional effect of these new analogs in vivo, with Pressure-Volume curve device, and to further test their comparative cardioprotective potential during experimental CLP sepsis.

Grant Acknowledgment

nHSF, Merck

References

  1. 1.

    Lesur O, Chagnon F, Murza A, Sarret P, Marsault E, Salvail D: Apelin is cardioprotective and life-saving over dobutamine in a murine model of endotoxin-induced myocardial dysfunction. Intensive Care Med Exp. 2014, 2 (Suppl 1): P11-10.1186/2197-425X-2-S1-P11. 0100

  2. 2.

    Murza A, Besserer-Offroy É, Côté J, Bérubé P, Longpré JM, Dumaine R, et al: C-Terminal modifications of apelin-13 significantly change ligand binding, receptor signaling, and hypotensive action. J Med Chem. 2015, 58 (5): 2431-2440. 10.1021/jm501916k.

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Author information

Correspondence to O Lesur.

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Keywords

  • Dobutamine
  • Myocardial Injury
  • Cardioprotective Effect
  • Myocardial Dysfunction
  • Unnatural Amino Acid