Structural and functional impairment of mitochondria in adriamycin-inducedcardiomyopathy in mice: Suppression of cytochrome c oxidase II gene expression
Lc. Papadopoulou et al., Structural and functional impairment of mitochondria in adriamycin-inducedcardiomyopathy in mice: Suppression of cytochrome c oxidase II gene expression, BIOCH PHARM, 57(5), 1999, pp. 481-489
The use of adriamycin (ADR) in cancer chemotherapy has been limited due to
its cumulative cardiovascular toxicity. Earlier observations that ADR inter
acts with mitochondrial cytochrome c oxidase (COX) and suppresses its enzym
e activity led us to investigate ADR's action on the cardiovascular functio
ns and heart mitochondrial morphology in Balb-c mice i.p. treated with ADR
for several weeks. At various times during treatment, the animals were asse
ssed fur cardiovascular functions by electrocardiography and for heart tiss
ue damage by electron microscopy. In parallel, total RNA was extracted from
samples of dissected heart and analyzed by Northern blot hybridization re,
determine the steady-state level oi three RNA transcripts encoded by the C
OXII, COXIII, and COXIV genes. Similarly, samples obtained from the liver o
f the same animals were analyzed for comparative studies. Our results indic
ated that 1) treatment of mice with ADR caused cardiovascular arrhythmias c
haracterized by bradycardia, extension oi ventricular depolarization time (
tQRS), and failure of QRS at high concentrations (10-14 mg/kg body weight c
umulative dose); 2) the heart mitochondria underwent swelling, fusion, diss
olution, and/or disruption of mitochondrial cristae after several weeks of
treatment. Such abnormalities were not observed in the mitochondria of live
r tissue; and 3) among the three genes of COX enzyme examined, only COXII g
ene expression was suppressed by ADR treatment, mainly after 8 weeks in bot
h heart and liver. Knowing that heart mitochondria represent almost 40% of
heart muscle by weight, we conclude that the deteriorating effects of ADR o
n cardiovascular function involve mitochondrial structural and functional i
mpairment. BIOCHEM PHARMACOL 57;5:481-489, 1999. (C) 1999 Elsevier Science
Inc.