Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction |
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Authors: | Annemieke van Dijk Paul A J Krijnen Rob A Vermond Amanda Pronk Marieke Spreeuwenberg Frans C Visser Richard Berney Walter J Paulus C Erik Hack Florine J van Milligen Hans W M Niessen |
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Institution: | 1. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands 7. ICaR-VU—Institute for Cardiovascular Research, VU Medical Center, Amsterdam, The Netherlands 6. Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands 3. Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands 8. Richard Berney Associates, LLC, Bethesda, MD, USA 4. Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands 5. Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands 2. Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands
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Abstract: | During acute myocardial infarction (AMI), ischemia leads to necrotic areas surrounded by border zones of reversibly damaged
cardiomyocytes, showing membrane flip-flop. During reperfusion type IIA secretory phopholipase A2 (sPLA2-IIA) induces direct cell-toxicity and facilitates binding of other inflammatory mediators on these cardiomyocytes. Therefore,
we hypothesized that the specific sPLA2-IIA-inhibitor PX-18 would reduce cardiomyocyte death and infarct size in vivo. Wistar rats were treated with PX-18 starting
minutes after reperfusion, and at day 1 and 2 post AMI. After 28 days hearts were analyzed. Furthermore, the effect of PX-18
on membrane flip-flop and apoptosis was investigated in vitro. PX-18 significantly inhibited sPLA2-IIA activity and reduced infarct size (reduction 73 ± 9%, P < 0.05), compared to the vehicle-treated group, without impairing wound healing. In vitro, PX-18 significantly reduced reversible
membrane flip-flop and apoptosis in cardiomyocytes. However, no sPLA2-IIA activity could be detected, suggesting that PX-18 also exerted a protective effect independent of sPLA2-IIA. In conclusion, PX-18 is a potent therapeutic to reduce infarct size by inhibiting sPLA2-IIA, and possibly also by inhibiting apoptosis of cardiomyocytes in a sPLA2-IIA independent manner.
A. van Dijk and P. A. J. Krijnen have contributed equally to the study. |
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Keywords: | Myocardial infarction Inflammation Ischemia reperfusion injury Secretory phopholipase A2 Apoptosis |
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