Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction.
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.
van Dijk
Annemieke
A
Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. annemieke.vandijk@vumc.nl
Krijnen
Paul A J
PA
Vermond
Rob A
RA
Pronk
Amanda
A
Spreeuwenberg
Marieke
M
Visser
Frans C
FC
Berney
Richard
R
Paulus
Walter J
WJ
Hack
C Erik
CE
van Milligen
Florine J
FJ
Niessen
Hans W M
HW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors*; D006334:Heart Function Tests; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects
D004791:Enzyme Inhibitors; D019821:Simvastatin; D054501:Group II Phospholipases A2; D053148:Caspase 3