Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction.

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 A(2) (sPLA(2)-IIA) induces direct cell-toxicity and facilitates binding of other inflammatory mediators on these cardiomyocytes. Therefore, we hypothesized that the specific sPLA(2)-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 sPLA(2)-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 sPLA(2)-IIA activity could be detected, suggesting that PX-18 also exerted a protective effect independent of sPLA(2)-IIA. In conclusion, PX-18 is a potent therapeutic to reduce infarct size by inhibiting sPLA(2)-IIA, and possibly also by inhibiting apoptosis of cardiomyocytes in a sPLA(2)-IIA independent manner.

• 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
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 14 Issue 6 Pg. 753-63 (Jun 2009) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 19421861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Simvastatin
• Group II Phospholipases A2
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Membrane (drug effects, enzymology)
• Cell Movement (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Group II Phospholipases A2 (antagonists & inhibitors)
• Heart Function Tests
• Immunohistochemistry
• Macrophages (cytology, drug effects, enzymology)
• Myocardial Infarction (enzymology, pathology, physiopathology)
• Myocytes, Cardiac (cytology, drug effects, enzymology)
• Neutrophils (cytology, drug effects, enzymology)
• Rats
• Rats, Wistar
• Simvastatin (pharmacology)
• Solubility (drug effects)