Chronic cholestasis and cardiac mitochondrial function in Wistar rats: a model for cardiovascular alterations in chronic liver disease?
OBJECTIVE
A growing number of reports in the literature have been correlating cardiovascular alterations with the presence of chronic liver disease, such as cirrhosis and cholestasis. The objective of this work was to compare mitochondrial bioenergetics and calcium loading capacity in the hearts of rats injected with alpha-naphthylisothiocyanate (ANIT), a compound used to induce cholestasis in animal models.


METHODS
Female Wistar rats (n = 12) were randomly divided into two groups. One of the groups was injected with six weekly doses of ANIT. Each group was evaluated in terms of mitochondrial bioenergetic capacity and susceptibility to the mitochondrial permeability transition (MPT), a deleterious phenomenon associated with oxidative stress and excessive mitochondrial calcium accumulation.


RESULTS
Our data showed unequivocally that cardiac mitochondria of rats chronically injected with ANIT lost their ability to accumulate calcium, in a cyclosporin A sensitive manner. This was reflected in a higher calcium-dependent swelling rate and amplitude (p < 0.01). The RCI value, an index of mitochondrial integrity, was also lower in the ANIT-treated group (p < 0.05).


CONCLUSIONS
This suggests that during cholestasis development, cardiac mitochondria lose their normal ability to control cytosolic calcium due to increased susceptibility to the MPT. Our results may suggest an explanation for the occurrence of cardiomyopathies associated with cholestatic disease, which may persist even in the absence of serum markers for liver disease.
Oliveira
Paulo J
PJ
Centro de Neurociências e Biologia Celular de Coimbra, Unidade de Investigação Básica em Cardiologia, Universidade de Coimbra, Coimbra, Portugal. pauloliv@ci.uc.pt
Rolo
Anabela P
AP
Seiça
Raquel
R
Santos
Maria S
MS
Palmeira
Carlos M
CM
Moreno
António J
AJ
D015058:1-Naphthylisothiocyanate / Q000008:administration & dosage; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology; D002779:Cholestasis / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000150:complications / Q000503:physiopathology; D008107:Liver Diseases / Q000150:complications / Q000503:physiopathology; D008929:Mitochondria, Heart / Q000502:physiology*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar
D015058:1-Naphthylisothiocyanate; D016572:Cyclosporine; D002118:Calcium