CARDIAC-MUSCLE PROTEIN GENE-EXPRESSION IN THE ENDOTOXIN-TREATED RAT

1. Sepsis is associated with marked changes in cardiac muscle protein synthesis. Such changes may be the result of altered transcription of specific myofibrillar protein mRNAs. 2. In order to investigate myofib rillar protein gene expression, a rat model of sepsis was used. Adult rats were given a single sub-lethal dose of lipopolysaccharide by the intraperitoneal route. At various times thereafter, rats were killed a nd ventricular muscle was removed. RNA was extracted and transferred t o nylon membranes. Changes in expression of mRNA for alpha- and beta-m yosin heavy chain, alpha-actin, cardiac troponin C and carbonic anhydr ase III were detected by Northern hybridization. 3. After treatment wi th lipopolysaccharide, mRNA for beta-myosin heavy chain increased to 2 60% of control values at 24 h and reached a maximum of 310% at 48 h. a lpha-Myosin heavy chain mRNA levels fell to 72%, of control values at 24 h. mRNA levels for alpha-actin, cardiac troponin C and carbonic anh ydrase III remained unchanged. 4. In order to investigate the role of tumour necrosis factor-alpha in this process, some rats were pretreate d with monoclonal antibody against tumour necrosis factor-alpha before receiving lipopolysaccharide. Such animals showed an absence of tumou r necrosis factor-alpha bioactivity in plasma, but changes in myocardi al protein mRNA levels were no different from those seen in animals re ceiving lipopolysaccharide alone. 5. The reduction in protein synthesi s in cardiac muscle in sepsis does not appear to be the result of redu ced expression of genes for structural or soluble muscle protein. Rath er there is a paradoxical increase in beta-myosin heavy chain expressi on, which may represent a protective mechanism. Tumour necrosis factor -alpha does not appear to be involved in the mediation of these change s.