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 flipflop 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.

The sPLA 2 Inhibition to Decrease Enzyme Release After Percutaneous Coronary Intervention (SPIDER-PCI) Trial

“…35 Inhibition of sPLA 2 -IIA has been shown to reduce infarct size by 70% in a rat model of ischemia/reperfusion. 13 In the present study, we did not demonstrate a beneficial effect of sPLA 2 inhibition on myocardial injury after elective PCI. There are several possible reasons why this result is discordant with prior observations in experimental ischemia/ reperfusion.…”

“…Furthermore, sPLA 2 -IIa has been shown to bind to the membrane of reversibly flip-flopped cardiomyocytes in border zones of experimental myocardial infarction, inducing cell death, whereas treatment with a specific inhibitor of sPLA 2 -IIA has been shown to inhibit this binding and to reduce experimental infarct size. 13 These data support the notion that sPLA 2 inhibition may reduce myocardial injury after PCI. A-002 (varespladib, Anthera Pharmaceuticals Inc, Hayward, Calif) is a smallmolecule agent, 1-h-indole-3-glyoxamide, which is rapidly metabolized to A-001, a potent inhibitor of sPLA 2 groups IIa, V, and X.…”

Comparison of docosahexaenoic acid uptake in murine cardiomyocyte culture and tissue: Significance to physiologically relevant studies

“…It is noteworthy that activated sPLA 2 has been found in human infarcted myocardia [21] and in rat hearts [22] and that Niessen et al [23] suggested that binding of sPLA2-II may be one of the earliest phenomena on the outside of cells during apoptosis and ischemia. In support of the sPLA 2 hypothesis, the authors recently reported that sPLA 2 in culprit coronary lesions is associated with myocardial infarction [24] and that its inhibition reduces death of cardiomyocytes in acute myocardial infarction [25]. In synthesis, accumulating evidence suggests that omega 3 fatty acids, notably DHA, exert anti-inflammatory actions also because of their inhibition of sPLA 2 in cardiovascular cells.…”

Endogenous κ-Opioid Peptide Mediates the Cardioprotection Induced by Ischemic Postconditioning

“…Apoptosis is a significant component of cell loss during reperfusion after myocardial infarction. 3 Although apoptosis in reperfusion injury is minor compared with necrosis, as indicated by the reduced markers of necrosis [enzyme release and infarct size (IS)], apoptosis is a highly regulated process, which is a good potential target for therapeutic intervention. Postcon may limit all forms of cell death (apoptosis, autophagy, and necrosis) induced by I/R.…”