Nuclear factor-kappaB inhibition improves myocardial contractility in rats with cirrhotic cardiomyopathy.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Liu
Hongqun
H
Liver Unit, University of Calgary, Calgary, AB, Canada.
Lee
Samuel S
SS
D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016328:NF-kappa B