Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia

Georg Baumgarten, Pascal Knuefermann, Gerrit Schuhmacher, Volker Vervölgyi, Joscha Von Rappard, Ulrike Dreiner, Klaus Fink, Chryso Djoufack, Andreas Hoeft, Christian Grohé, Anne A Knowlton, Rainer Meyer

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

The molecular mechanisms that mediate gram-negative sepsis-associated myocardial dysfunction remain elusive. Myocardial expression of inflammatory mediators is Toll-like receptor 4 (TLR4) dependent. However, it remains to be elucidated whether TLR4, expressed on cardiac myocytes, mediates impairment of cardiac contractility after lipopolysaccharide (LPS) application. Cardiac myocyte contractility, measured as sarcomere shortening of isolated cardiac myocytes from C3H/HeJ (with nonfunctional TLR4) and C3H/HeN (control), were recorded at stimulation frequencies between 0.5 and 10 Hz and after incubation with 1 and 10 μg/mL LPS for up to 8 h. Control cells treated with LPS were investigated with and without a competitive LPS inhibitor (E5564) and a specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea. In control mice, LPS reduced sarcomere shortening amplitude and prolonged duration of relaxation, whereas sarcomere shortening of C3H/HeJ cells was insensitive to LPS. NFκB and iNOS were upregulated after LPS application in control mice compared with C3H/HeJ. Inhibition of TLR4 by E5564 as well as inhibition of iNOS prevented the influence of LPS on contractile activity in control myocytes. LPS-dependent suppression of cardiac myocyte contractility was significantly blunted in C3H/HeJ mice. Competitive inhibition of functional TLR4 with E5564 protects cardiac myocyte contractility against LPS. These findings suggest that TLR4, expressed on cardiac myocytes, contributes to sepsis-induced myocardial dysfunction. E5564, currently under investigation in two clinical phase II trials, seems to be a new therapeutic option for the treatment of myocardial dysfunction in sepsis associated with endotoxemia.

Original languageEnglish (US)
Pages (from-to)43-49
Number of pages7
JournalShock
Volume25
Issue number1
DOIs
StatePublished - Jan 2006

Keywords

  • Cardiac myocyte contractility
  • E5564
  • LPS
  • Myocardial depression
  • Sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Physiology

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