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Keywords:

  • cell shortening;
  • cirrhosis;
  • cytokine;
  • diastolic;
  • heart;
  • NF-κB;
  • systolic;
  • TNF-α

Abstract

Background/Aims: Cytokines such as tumour necrosis factor (TNF-α) contribute to the pathogenesis of cirrhotic cardiomyopathy. Nuclear factor-κB (NF-κB) is crucial for cytokine regulation, and induces cardiac dysfunction in several heart disease models. We aimed to elucidate possible NF-κB involvement in cirrhotic cardiomyopathy.

Methods: Rats were bile duct ligated (BDL) to produce cirrhosis; controls received sham operation. Animals were studied 4 weeks later. Two NF-κB inhibitors were used: pyrrolidine dithiocarbamate (PDTC) and Bay 11-7082. Four groups were studied in most protocols: sham control, sham+PDTC, BDL and BDL+PDTC. Additional contractility studies were performed with Bay 11-7082. Myocardial NF-κB and TNF-α expression was measured by Western blot and ELISA. The contractility of isolated cardiomyocytes was observed under direct microscopy.

Results: Nuclear factor-κB and TNF-α levels were increased in cirrhotic hearts compared with controls. PDTC significantly reduced NF-κB activity and TNF-α expression in cirrhotic hearts; controls were unaffected. Cirrhotic cardiomyocytes showed decreased systolic and diatolic velocity compared with sham controls. Both PDTC and Bay 11-7082 restored contractile function in cirrhotic cardiomyocytes, but did not affect controls.

Conclusions: Inhibition of the increased NF-κB activity in cirrhotic hearts was associated with improvement of attenuated cardiomyocyte contractility. NF-κB, via effects on cytokine expression, may contribute to the pathogenesis of cirrhotic cardiomyopathy.