Changes in phospholipid content and myocardial calcium-independent phospholipase A2 activity during chronic anthracycline administration.

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 A(2) (iPLA(2)) activity both in vitro and in vivo. This study presents data that iPLA(2) 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 iPLA(2) activity. Membrane-associated iPLA(2) 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 iPLA(2) 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 iPLA(2) inhibition may be one of the steps that leads to the functional and structural changes associated with chronic anthracycline treatment.