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

• Published in: Nature (London) Vol. 390; no. 6660; pp. 622 - 625
• Main Authors: BONVENTRE, J. V, HUANG, Z, TAHERI, M. R, O'LEARY, E, LI, E, MOSKOWITZ, M. A, SAPIRSTEIN, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 11.12.1997; Nature Publishing Group
• Subjects: Analytical, structural and metabolic biochemistry; Animal reproduction; Animals; Biological and medical sciences; Brain Edema - enzymology; Brain Ischemia - enzymology; Brain Ischemia - pathology; Cerebral Infarction - enzymology; Cerebral Infarction - pathology; Cerebrovascular Circulation; Cytosol - enzymology; Enzymes; Enzymes and enzyme inhibitors; Female; Fundamental and applied biological sciences. Psychology; Head injuries; Heterozygote; Homozygote; Humans; Hydrolases; Infertility - enzymology; Litter Size; Macrophages, Peritoneal - metabolism; Male; Mice; Mice, Knockout; Neurology; Phospholipases A - deficiency; Phospholipases A - genetics; Phospholipases A - physiology; Phospholipases A2; Pregnancy; Rodents; Cardiovascular disease; Esterases; Vascular disease; Reproduction; Ischemia; Investigation method; Fertility; Cerebrovascular disease; Nervous system diseases; Enzyme; Arachidonic acid derivatives; Rodentia; Inflammation; Phospholipase A; Biological activity; Carboxylic ester hydrolases; Cerebral disorder; In vivo; Leukotriene; Vertebrata; Mammalia; Mouse; Central nervous system disease; Hydrolases; Brain (vertebrata); Macrophage
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/37635

Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis and can directly modify the composition of cellular membranes. 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 inflammation, reproduction and neurotoxicity. 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 concentration. 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.