Abstract

Despite numerous investigations, the causes underlying anthracycline cardiomyopathy are yet to be established. We have recently reported that acute treatment with anthracyclines inhibits membrane-associated calcium-independent phospholipase A₂ (iPLA₂) activity both in vitro and in vivo. This study presents data that iPLA₂ activity is also suppressed during chronic drug administration. Adult Sprague-Dawley rats were given weekly 1 mg/kg i.v. injections of doxorubicin for a total of 8 weeks. One week after the last injection, the animals were sacrificed, and heart tissue was assessed for phospholipid content and iPLA₂ activity. Membrane-associated iPLA₂ activity in the myocardium of doxorubicin-treated animals was 40% lower than that in control hearts. In addition, doxorubicin treatment resulted in significant alterations in the distribution of fatty acyl moieties esterified to the sn-2 position of choline glycerophospholipids. The ethanolamine species remained unaffected. Elevation in the amount of arachidonate and linoleate esterified to the sn-2 position of choline plasmalogens was consistent with the hypothesis that iPLA₂ displays selectivity for plasmalogen phospholipids; therefore, enzyme inhibition may affect hydrolysis of these phospholipid subclasses. Notably, the changes in phospholipid content occurred at a low cumulative dose of 8 mg/kg at which appearance of structural lesions was minimal. Therefore, these alterations seem to be both specific and early signs of cardiomyocyte pathology. The results support our hypothesis that myocardial iPLA₂ inhibition may be one of the steps that leads to the functional and structural changes associated with chronic anthracycline treatment.