Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: Interaction between TNFα and endocannabinoids
Received 8 December 2009; received in revised form 23 February 2010; accepted 8 March 2010. published online 14 May 2010.
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.
1Liver Unit, Faculty of Medicine, University of Calgary, Calgary, Canada
2Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan
3Department of Preventive Medicine, Institute of Public Health, National Yang-Ming University School of Medicine, Taipei, Taiwan
4Laboratory of Physiologic Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
Corresponding author. Address: Health Science Centre, 3330 Hospital Dr NW, Calgary, AB, Canada T2N 4N1. Fax: +1 403 270 0995.
† These two authors contributed equally to this paper.
ABSTRACT