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.
Footnotes
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This work was supported by National Institutes of Health Grants HL68588 (to J.M.) and HL62419 (to N.A.S.).
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doi:10.1124/jpet.104.069419.
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ABBREVIATIONS: iPLA2, calcium-independent phospholipase A2; AIPI, anthracycline-induced phospholipase A2 inhibition; PLA2, phospholipase A2; HPLC, high-performance liquid chromatography; CGP, choline glycerophospholipid; EGP, ethanolamine glycerophospholipid; PVDF, polyvinylidene difluoride; cis-UFA PLD, cis-unsaturated fatty acid-sensitive form of phospholipase D.
- Received April 3, 2004.
- Accepted August 4, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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