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Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2

Abstract

Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis and can directly modify the composition of cellular membranes1,2. PLA2 enzymes release fatty acids and lysophospholipids, including the precursor of platelet-activating factor, PAF, from phospholipids. Free fatty acids, eicosanoids, lysophospholipids and PAF are potent regulators of inflammation1,3,4, reproduction5,6,7 and neurotoxicity1,8,9. The physiological roles of the various forms of PLA2 are not well defined. The cytosolic form, cPLA2, preferentially releases arachidonic acid from phospholipids and is regulated by changes in intracellular calcium concentration10,11. We have now created ‘knockout’ (cPLA2−/−) mice that lack this enzyme, in order to evaluate its physiological importance. We find that cPLA2−/− mice develop normally, but that the females produce only small litters in which the pups are usually dead. Stimulated peritoneal macrophages from cPLA2−/− animals did not produce prostaglandin E2 or leukotriene B4 or C4. After transient middle cerebral artery occlusion, cPLA2−/− mice had smaller infarcts and developed less brain oedema and fewer neurological deficits. Thus cPLA2 is important for macrophage production of inflammatory mediators, fertility, and in the pathophysiology of neuronal death after transient focal cerebral ischaemia.

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Figure 1: Targeting strategy for inactivation of the cPLA2 gene and the resulting DNA and protein analysis.
Figure 2: Metabolic and synthetic function is altered in peritoneal macrophages of −/− mice.
Figure 3: Middle cerebral artery (MCA) occlusion results in smaller infarcts in knockout mice.

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Acknowledgements

We thank J. Newell, Y. Kang, F. Chilton and A. Fanteh for discussion and A. Cybulsky for the gift of anti-cPLA2 antibody. J.V.B. is a MERIT Awardee of the NIH; A.S. is a Foundation for Anesthesia Education and Research investigator. This work was supported by grants from the NIH, including the MGH Interdepartmental Stroke Program Project.

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Correspondence to Joseph V. Bonventre.

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Bonventre, J., Huang, Z., Taheri, M. et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390, 622–625 (1997). https://doi.org/10.1038/37635

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