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Type II secretory phospholipase A₂ binds to ischemic flip-flopped cardiomyocytes and subsequently induces cell death

Departments of ¹Pathology, ²Cardiology, ³Clinical Chemistry, ⁴Physiology, and ⁵Gynecology, Vrije Universiteit Medical Center, and ⁶Institute for Cardiovascular Research, Vrije Universiteit, 1007 MB Amsterdam, The Netherlands; ⁷Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037; and ⁸Sanquin Reseach, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Department of Immunopathology, 1006 AN Amsterdam, The Netherlands

Submitted 8 October 2002 ; accepted in final form 3 June 2003

Type II secretory phospholipase A₂ (sPLA₂) is a cardiovascular risk factor. We recently found depositions of sPLA₂ in the necrotic center of infarcted human myocardium and normally appearing cardiomyocytes adjacent to the border zone. The consequences of binding of sPLA₂ to ischemic cardiomyocytes are not known. To explore a potential effect of sPLA₂ on ischemic cardiomyocytes at a cellular level we used an in vitro model. The cardiomyocyte cell line H9c2 or adult cardiomyocytes were isolated from rabbits that were incubated with sPLA₂ in the presence of metabolic inhibitors to mimic ischemia-reperfusion conditions. Cell viability was established with the use of annexin V and propidium iodide or 7-aminoactinomycin D. Metabolic inhibition induced an increase of the number of flip-flopped cells, including a population that did not stain with propidium iodide and that was caspase-3 negative. sPLA₂ bound to the flip-flopped cells, including those negative for caspase-3. sPLA₂ binding induced cell death in these latter cells. In addition, sPLA₂ potentiated the binding of C-reactive protein (CRP) to these cells. We conclude that by binding to flip-flopped cardiomyocytes, including those that are caspase-3 negative and presumably reversibly injured, sPLA₂ may induce cell death and tag these cells with CRP.

myocardial infarction; inflammation

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