Partial inhibition of protein synthesis by Pseudomonas exotoxin A deranges catecholamine sensitivity of cultured rat heart myocytes

J Mol Cell Cardiol. 1997 Feb;29(2):799-811. doi: 10.1006/jmcc.1996.0324.

Abstract

To elucidate cellular mechanisms of myocardial depression in Pseudomonas sepsis the effects of sublethal concentrations of P. aeruginosa exotoxin A--a main virulence factor--were studied in cultured neonatal rat cardiomyocytes. It is known that this toxin exerts its pathogenic effect by inhibition of protein synthesis via ADP-ribosylation and thereby inactivation of elongation factor 2 (EF-2). Within 48 72 h, half maximal inhibition of protein synthesis occurs at 4-10 ng/ml. The toxin prevents the beta-adrenoceptor(AR)-mediated myosin heavy chain isozyme shift (V3/V1), while the T3-induced myosin shift is not suppressed. While beta 1-AR-downregulation by excess of norepinephrine (NE) is not affected, protein synthesis-dependent receptor upregulation in the recover period after removal of NE is completely suppressed by P. aeruginosa exotoxin A. Thus, a non-lethal, partial inhibition of global cellular protein synthesis by P. aeruginosa exotoxin A: (1) completely prevents beta 1-AR-mediated myosin isozyme shift and beta-AR upregulation: (2) sustains the cardiomyocytes in a catecholamine-refractory contractile state in the recovery period after catecholamine desensitization: (3) suggests cellular mechanisms by which P. aeruginosa exotoxin A might impair heart function in Pseudomonas sepsis: and (4) may help reveal the possible influence of endogenous inhibitors of EF-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases*
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Bacterial Toxins*
  • Catecholamines / pharmacology*
  • Cells, Cultured
  • Cytotoxins / toxicity
  • Dose-Response Relationship, Drug
  • Exotoxins / pharmacology*
  • Exotoxins / toxicity
  • Isoproterenol / pharmacology
  • Myocardial Contraction / drug effects
  • Myocardium / cytology*
  • Myocardium / metabolism
  • Norepinephrine / pharmacology
  • Protein Biosynthesis*
  • Proteins / drug effects
  • Pseudomonas aeruginosa Exotoxin A
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta-1 / drug effects
  • Receptors, Adrenergic, beta-1 / metabolism
  • Triiodothyronine / pharmacology
  • Virulence Factors*

Substances

  • Adrenergic alpha-Agonists
  • Adrenergic beta-Agonists
  • Bacterial Toxins
  • Catecholamines
  • Cytotoxins
  • Exotoxins
  • Proteins
  • Receptors, Adrenergic, beta-1
  • Virulence Factors
  • Triiodothyronine
  • ADP Ribose Transferases
  • Isoproterenol
  • Norepinephrine