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Cardioprotective effects of irbesartan in polymicrobial sepsis

The role of the p38MAPK/NF-κB signaling pathway

Kardioprotektive Wirkungen von Irbesartan bei polymikrobieller Sepsis

Bedeutung des p38MAPK/NF-κB-Signalwegs

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Abstract

Background

Sepsis is a systemic inflammatory response usually correlated with multi-organ failure. Myocardial dysfunction is one of the adverse outcomes in septic patients and results in high mortality rates. The aim of this study was to investigate the impact of irbesartan in attenuation of cardiac depression during polymicrobial sepsis via decreased activation of the phospho-p38MAPK/nuclear factor (NF)-κB signaling pathway.

Materials and methods

A model of polymicrobial sepsis induced via cecal ligation and puncture (CLP) with 8- to 12-week-old albino mice was used. Mice were treated with i.p. irbesartan (3 mg/kg) 1 h before CLP. Using a micro-tipped transducer catheter, the following hemodynamic parameters were evaluated after CLP: heart rate, ejection fraction, left ventricular (LV) end-diastolic pressure, LV systolic pressure, and cardiac output. Plasma levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), and cardiac troponin I (cTn-I), were measured via ELISA analysis. The degree of p38MAPK and NF-κB phosphorylation was assessed via Western blotting.

Results

Mice treated with irbesartan displayed improvement in LV function (ejection fraction: 42.4 ± 1.1% vs. 27.8 ± 3% in CLP mice). The attenuation of cardiac depression in irbesartan-treated mice was associated with lower levels of MCP-1 in plasma and a reduction in the levels of TNF-alpha, IL-1beta, and IL-6. Furthermore, irbesartan-treated mice displayed lower expression levels of p38-MAPK and NF-κB phosphorylation.

Conclusion

Irbesartan can attenuate cardiac dysfunction during polymicrobial sepsis possibly via a reduction of proinflammatory cytokines through decreased activation of the p38MAPK/NF-κB pathways.

Zusammenfassung

Hintergrund

Die Sepsis stellt eine systemische entzündliche Reaktion dar, die gewöhnlich mit Multiorganversagen einhergeht. Myokardfunktionsstörungen sind eine der ungünstigen Folgen bei septischen Patienten und führen zu einer hohen Mortalitätsrate. Ziel der vorliegenden Studie war es, den Einfluss von Irbesartan auf die Abschwächung der Kreislaufdepression bei polymikrobieller Sepsis über eine verminderte Aktivierung des Signalwegs von Phospho-p38MAPK/Nuclear-Factor(NF)-κB zu untersuchen.

Material und Methoden

Es wurde ein Modell der polymikrobiellen Sepsis verwendet, bei dem die Sepsis über eine Ligatur und Punktur des Zoekums („cecal ligation and puncture“, CLP) bei 8–12 Wochen alten Albinomäusen induziert wurde. Die Mäuse wurden i.p. mit Irbesartan (3 mg/kg) 1 h vor CLP behandelt. Unter Einsatz eines Mikrotip-Transducer-Katheters wurden die folgenden hämodynamischen Parameter nach CLP gemessen: Herzfrequenz, Ejektionsfraktion, linksventrikulärer (LV) enddiastolischer Druck, LV systolischer Druck und Herzzeitvolumen. Mittels ELISA-Test wurden die Plasmaspiegel proinflammatorischer Zytokine einschließlich Tumornekrosefaktor-alpha (TNF-α), Interleukin-1beta (IL-1β), IL-6, Monozyten-chemoattraktives Protein-1 (MCP-1) und kardiales Troponin I (cTn-I) bestimmt. Der Grad der Phosphorylierung von p38MAPK und NF-κB wurde per Western-Blot-Test ermittelt.

Ergebnisse

Die mit Irbesartan behandelten Mäuse wiesen eine Verbesserung der LV-Funktion auf (Ejektionsfraktion: 42,4 ± 1,1% vs. 27,8 ± 3% bei CLP-Mäusen). Die Abschwächung der Kreislaufdepression bei den mit Irbesartan behandelten Mäusen ging mit niedrigeren Plasmaspiegeln von MCP-1 und einer Senkung der Werte für TNF-α, IL-1β und IL-6 einher. Darüber hinaus zeigten die mit Irbesartan behandelten Mäuse eine geringere Expression der Phosphorylierung von p38-MAPK und NF-κB.

Schlussfolgerung

Irbesartan kann möglicherweise über eine Verminderung proinflammatorischer Zytokine durch geringere Aktivierung des p38MAPK/NF-κB-Signalwegs zu einer Abschwächung der kardialen Funktionsstörung bei polymikrobieller Sepsis führen.

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Author information

Authors and Affiliations

  1. Department of Medicine, Muthanna Medical College, Samawah, Iraq

    N. G. Yousif

  2. Anschutz | Medical School, University of Colorado, Denver, USA

    N. G. Yousif

  3. Department of Pharmacology and Therapeutics, Kufa Medical College, University Kufa, Kufa, Iraq

    N. R. Hadi & Q. A. Zigam

  4. Department of Thoracic Surgery, Kufa Medical College, University Kufa, Kufa, Iraq

    F. Al-Amran

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  1. N. G. Yousif
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  2. N. R. Hadi
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  3. F. Al-Amran
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  4. Q. A. Zigam
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Correspondence to N. G. Yousif.

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Conflict of interest

N.G. Yousif, N.R. Hadi, F. Al-Amran, and Q.A. Zigam declare that they have no competing interests.

All national guidelines on the care and use of laboratory animals have been followed and that the necessary approval was obtained from the relevant authorities.

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Yousif, N.G., Hadi, N.R., Al-Amran, F. et al. Cardioprotective effects of irbesartan in polymicrobial sepsis. Herz 43, 140–145 (2018). https://doi.org/10.1007/s00059-017-4537-6

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  • DOI: https://doi.org/10.1007/s00059-017-4537-6

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