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CARDIOVASCULAR

Changes in Phospholipid Content and Myocardial Calcium-Independent Phospholipase A₂ Activity during Chronic Anthracycline Administration

Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas (L.M.S., N.A.S.); and Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri (J.M., K.N.C.)

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.

Address correspondence to: Dr. Narine Sarvazyan, Department of Physiology, Texas Tech University Health Sciences Center, 3601 4th St., Lubbock, TX 79430. E-mail: narine.sarvazyan{at}ttuhsc.edu

This article has been cited by other articles:

				L. Gianni, E. H. Herman, S. E. Lipshultz, G. Minotti, N. Sarvazyan, and D. B. Sawyer Anthracycline Cardiotoxicity: From Bench to Bedside J. Clin. Oncol., August 1, 2008; 26(22): 3777 - 3784. [Abstract] [Full Text] [PDF]