Nuclear factor‐κB inhibition improves myocardial contractility in rats with cirrhotic cardiomyopathy

Abstract

Cytokines such as tumour necrosis factor (TNF-alpha) contribute to the pathogenesis of cirrhotic cardiomyopathy. Nuclear factor-kappaB (NF-kappaB) is crucial for cytokine regulation, and induces cardiac dysfunction in several heart disease models. We aimed to elucidate possible NF-kappaB involvement in cirrhotic cardiomyopathy. Rats were bile duct ligated (BDL) to produce cirrhosis; controls received sham operation. Animals were studied 4 weeks later. Two NF-kappaB 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-kappaB and TNF-alpha expression was measured by Western blot and ELISA. The contractility of isolated cardiomyocytes was observed under direct microscopy. Nuclear factor-kappaB and TNF-alpha levels were increased in cirrhotic hearts compared with controls. PDTC significantly reduced NF-kappaB activity and TNF-alpha 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. Inhibition of the increased NF-kappaB activity in cirrhotic hearts was associated with improvement of attenuated cardiomyocyte contractility. NF-kappaB, via effects on cytokine expression, may contribute to the pathogenesis of cirrhotic cardiomyopathy.