Partial inhibition of protein synthesis by Pseudomonas exotoxin A deranges catecholamine sensitivity of cultured rat heart myocytes.
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.
Müller-Werdan
U
U
Department of Medicine III, University of Halle-Wittenberg, Klinikum Kröllwitz, Halle, Germany.
Pfeifer
A
A
Hübner
G
G
Seliger
C
C
Reithmann
C
C
Rupp
H
H
Werdan
K
K
D036002:ADP Ribose Transferases; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins; D002395:Catecholamines / Q000494:pharmacology*; D002478:Cells, Cultured; D003603:Cytotoxins / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000494:pharmacology* / Q000633:toxicity; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D001427:Bacterial Toxins; D002395:Catecholamines; D003603:Cytotoxins; D005098:Exotoxins; D007545:Isoproterenol; D009638:Norepinephrine; D011506:Proteins; D018342:Receptors, Adrenergic, beta-1; D014284:Triiodothyronine; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A