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MYOCARDIAL APOPTOSIS AND PATHOGENESIS OF CIRRHOTIC CARDIOMYOPATHY
H Liu, A Feng, JZ Wang, SS Lee
Liver Unit, Department of Medicine, University of Calgary, Calgary, Alberta
Background and AIM: Cirrhotic cardiomyopathy is defined as systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. The mechanism is not clear. Apoptosis is known to be associated with cardiac dysfunction. Our hypothesis is that apoptosis signaling activation participates in cardiac dysfunction in cirrhotic cardiomyopathy. We therefore evaluated apoptosis pathways in cirrhotic hearts.
Material and METHODS: Cirrhotic cardiomyopathy model was induced with bile duct ligation in rats. Briefly, Sprague-Dawley rats were anaesthetized with phenobartital and the bile ducts were exposed through a midline incision. After double bile duct ligation, the bile duct was cut between the two ligatures. The heart was harvested 4 weeks after surgery. The apoptotic pathway, including the extrinsic and intrinsic pathways, was evaluated by RT-PCR for mRNA transcription evaluation and western blots for protein expression.
RESULTS: in cirrhotic hearts, the proapoptotic factors of the extrinsic pathway (such as Fas) were activated while the antiapoptotic factors (such as FLIP) were decreased compared with sham control. The intrinsic pathway does not play an important role. BCL2/Bax/ mRNA transcription was increased in BDL which suggests that in cirrhosis, the intrinsic pathway is trying to compensate for the net proapoptotic dominance. However, there was no significant change in protein level.
CONCLUSION: There are two known pathways to induce apoptosis, the extrinsic and intrinsic pathways. Our results indicate a net proapoptotic influence in cardiomyocytes, mainly mediated by the extrinsic pathway, while the intrinsic pathway does not play a major role. Further gene manipulation and functional studies are necessary to clarify which factor activation plays the essential role in apoptosis in cirrhotic cardiomyopathy.
