Cardiomyocyte apoptosis contributes to pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated mice.
Cirrhotic cardiomyopathy is defined as systolic and diastolic dysfunctions, electrophysiological changes and macroscopic structural changes. However, the underlying mechanisms of this syndrome remain unclear. A possible role of myocardial apoptosis in the pathogenesis has not been previously examined. We hypothesized that dysregulation of apoptotic signalling participates in cardiac dysfunction in the cirrhotic heart. Therefore, we evaluated apoptotic pathways in the hearts of mice with chronic BDL (bile duct ligation). A cirrhotic cardiomyopathy model was induced by BDL in mice. Left ventricular geometry and volumes were evaluated by MRI. Intrinsic and extrinsic apoptotic pathways were evaluated by immunohistochemical staining and Western blot analysis. Fas-mediated apoptosis was inhibited by in vivo administration of an anti-FasL (Fas ligand) monoclonal antibody, and subsequently cardiac contractility was measured in isolated cardiomyocytes. BDL-mice showed significantly more PARP [poly(ADP-ribose) polymerase] staining than sham controls (18.2±11.4 compared with 6.7±5.3; P<0.05). Fas protein expression and PARP cleavage were activated, whereas FLIP (Fas-associated death domain-like interleukin 1β-converting enzyme-inhibitory protein) was decreased compared with sham controls. The Bcl-2/Bax ratio was increased in BDL-mice compared with sham controls. Anti-FasL monoclonal antibody injection in BDL-mice improved systolic and diastolic dysfunctions in cardiomyocytes, but had no effect in sham controls. A net pro-apoptotic balance exists in BDL hearts, mainly mediated by activation of the extrinsic pathway, and abrogation of apoptosis improved contractility. These results suggest that apoptosis contributes to depressed cardiac contractility in a murine model of cirrhotic cardiomyopathy.
*Liver Unit, University of Calgary, Calgary, Canada.
Soon Woo
SW
Nam
*Liver Unit, University of Calgary, Calgary, Canada.
Hongqun
H
Liu
*Liver Unit, University of Calgary, Calgary, Canada.
Joe Z
JZ
Wong
*Liver Unit, University of Calgary, Calgary, Canada.
Annie Y
AY
Feng
†Stephenson MR Cardiovascular Unit, University of Calgary, Calgary, Canada.
Gavin
G
Chu
†Stephenson MR Cardiovascular Unit, University of Calgary, Calgary, Canada.
Naeem
N
Merchant
*Liver Unit, University of Calgary, Calgary, Canada.
Samuel S
SS
Lee
D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000473:pathology*; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000473:pathology*; D005355:Fibrosis; D007150:Immunohistochemistry; D008026:Ligation; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*