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 (TNFα)-nuclear factor κB (NFκB) pathway. However, how they interact with each other remains obscure. We therefore aimed to clarify the relationship between the TNFα-NFκB pathway and endocannabinoids in the pathogenesis of cardiodepression of cholestatic bile duct ligated (BDL) mice. Methods: BDL mice with TNFα knockout (TNFα-/-) and infusion of anti-TNFα antibody were used. Cardiac mRNA and protein expression of NFκBp65, c-Jun-N-terminal kinases (JNK), 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 TNFα were measured. The effects of TNFα, 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 NFκBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFα were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased. Cardiac contractility was blunted in BDL mice. Anti-TNFα treatment in BDL mice decreased cardiac anandamide and NOx, reduced expression of NFκBp65, p38MAPK, and iNOS, enhanced expression of Cu/Zn-SOD and Mn-SOD, increased reductive glutathione and restored cardiomyocyte contractility. TNFα-depressed contractility was worsened by UCM707, whereas AM251 improved contractility. Conclusions: Increased TNFα, acting via NFκB-iNOS and p38MAPK signaling pathways, plays an important role in the pathogenesis of cardiodepression in BDL mice. TNFα also suppressed contractility by increasing oxidative stress and endocannabinoid activity.