Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: Interaction between TNFα and endocannabinoids

Background & Aims: Chronic liver disease is associated with endotoxemia, oxidative stress, increased endocannabinoids and decreased cardiac responsiveness. Endocannabinoids activate the tumor necrosis factor-alpha (TNF alpha)-nuclear factor kappa B (NF kappa B) pathway. However, how they interact with each other remains obscure. We therefore aimed to clarify the relationship between the TNF alpha-NF kappa B pathway and endocannabinoids in the pathogenesis of cardiodepression of cholestatic bile duct ligated (BDL) mice. Methods: BDL mice with TNF alpha knockout (TNF alpha-/-) and infusion of anti-TNF alpha antibody were used. Cardiac mRNA and protein expression of NF kappa Bp65, c-Jun-N-terminal kinases (INK), p38 mitogen-activated protein kinase (p38MAPK), extracelullar-signal-regulated kinase (ERK), inducible nitric oxide synthase (iNOS), Copper/Zinc and Magnesium-superoxide dismutase (Cu/Zn- and Mn-SOD), cardiac anandamide, 2-arachidonoylglycerol (2-AG), nitric oxide (NOx) and glutathione, and plasma TNF alpha were measured. The effects of TNF alpha, cannabinoid receptor (CB1) antagonist AM251 and the endocannabinoid reuptake inhibitor UCM707, on the contractility of isolated cardiomyocytes, were assessed. Results: In BDL mice, cardiac mRNA and protein expression of NF kappa Bp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNF alpha were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased. Cardiac contractility was blunted in BDL mice. Anti-TNF alpha treatment in BDL mice decreased cardiac anandamide and NOx, reduced expression of NF kappa Bp65, p38MAPK, and iNOS, enhanced expression of Cu/Zn-SOD and Mn-SOD, increased reductive glutathione and restored cardiomyocyte contractility. TNF alpha-depressed contractility was worsened by UCM707, whereas AM251 improved contractility. Conclusions: Increased TNF alpha, acting via NF kappa B-iNOS and p38MAPK signaling pathways, plays an important role in the pathogenesis of cardiodepression in BDL mice. TNFa also suppressed contractility by increasing oxidative stress and endocannabinoid activity. (C) 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.