Phospholipase A 2, reactive oxygen species, and lipid peroxidation in cerebral ischemia

Abstract

Ischemic stroke is caused by obstruction of blood flow to the brain, resulting in energy failure that initiates a complex series of metabolic events, ultimately causing neuronal death. One such critical metabolic event is the activation of phospholipase A 2 (PLA 2), resulting in hydrolysis of membrane phospholipids and release of free fatty acids including arachidonic acid, a metabolic precursor for important cell-signaling eicosanoids. PLA 2 enzymes have been classified as calcium-dependent cytosolic (cPLA 2) and secretory (sPLA 2) and calcium-independent (iPLA 2) forms. Cardiolipin hydrolysis by mitochondrial sPLA 2 disrupts the mitochondrial respiratory chain and increases production of reactive oxygen species (ROS). Oxidative metabolism of arachidonic acid also generates ROS. These two processes contribute to formation of lipid peroxides, which degrade to reactive aldehyde products (malondialdehyde, 4-hydroxynonenal, and acrolein) that covalently bind to proteins/nucleic acids, altering their function and causing cellular damage. Activation of PLA 2 in cerebral ischemia has been shown while other studies have separately demonstrated increased lipid peroxidation. To the best of our knowledge no study has directly shown the role of PLA 2 in lipid peroxidation in cerebral ischemia. To date, there are very limited data on PLA 2 protein by Western blotting after cerebral ischemia, though some immunohistochemical studies (for cPLA 2 and sPLA 2) have been reported. Dissecting the contribution of PLA 2 to lipid peroxidation in cerebral ischemia is challenging due to multiple forms of PLA 2, cardiolipin hydrolysis, diverse sources of ROS arising from arachidonic acid metabolism, catecholamine autoxidation, xanthine oxidase activity, mitochondrial dysfunction, activated neutrophils coupled with NADPH oxidase activity, and lack of specific inhibitors. Although increased activity and expression of various PLA 2 isoforms have been demonstrated in stroke, more studies are needed to clarify the cellular origin and localization of these isoforms in the brain, their responses in cerebral ischemic injury, and their role in oxidative stress.