Mechanisms of TNFalpha-induced cardiac dysfunction in cholestatic bile duct-ligated mice: interaction between TNFalpha and endocannabinoids.
OBJECTIVE
Chronic liver disease is associated with endotoxemia, oxidative stress, increased endocannabinoids and decreased cardiac responsiveness. Endocannabinoids activate the tumor necrosis factor-alpha (TNFalpha)-nuclear factor kappaB (NFkappaB) pathway. However, how they interact with each other remains obscure. We therefore aimed to clarify the relationship between the TNFalpha-NFkappaB pathway and endocannabinoids in the pathogenesis of cardiodepression of cholestatic bile duct ligated (BDL) mice.


METHODS
BDL mice with TNFalpha knockout (TNFalpha-/-) and infusion of anti-TNFalpha antibody were used. Cardiac mRNA and protein expression of NFkappaBp65, 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 TNFalpha were measured. The effects of TNFalpha, 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 NFkappaBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFa were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased. Cardiac contractility was blunted in BDL mice. Anti-TNFa treatment in BDL mice decreased cardiac anandamide and NOx, reduced expression of NFkappaBp65, p38MAPK, and iNOS, enhanced expression of Cu/Zn-SOD and Mn-SOD, increased reductive glutathione and restored cardiomyocyte contractility. TNFa-depressed contractility was worsened by UCM707, whereas AM251 improved contractility.


CONCLUSIONS
Increased TNFalpha, acting via NFkappaB-iNOS and p38MAPK signaling pathways, plays an important role in the pathogenesis of cardiodepression in BDL mice. TNFalpha also suppressed contractility by increasing oxidative stress and endocannabinoid activity.
Yang
Ying-Ying
YY
Liver Unit, Faculty of Medicine, University of Calgary, Calgary, Canada.
Liu
Hongqun
H
Nam
Soon Woo
SW
Kunos
George
G
Lee
Samuel S
SS
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D002779:Cholestasis / Q000150:complications* / Q000209:etiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005663:Furans / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005663:Furans; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D016328:NF-kappa B; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; C103505:AM 251; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases