Secretory Phospholipase A2, Group IIA Is a Novel Serum Amyloid A Target Gene: ACTIVATION OF SMOOTH MUSCLE CELL EXPRESSION BY AN INTERLEUKIN-1 RECEPTOR-INDEPENDENT MECHANISM (original) (raw)
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eLife, 2019
Serum amyloid A (SAA) is an evolutionally conserved enigmatic biomarker of inflammation. In acute inflammation, SAA plasma levels increase ~1,000-fold suggesting a vital beneficial role. SAA increases simultaneously with secretory phospholipase A2 (sPLA2), compelling us to determine how SAA influences sPLA2 hydrolysis of lipoproteins. SAA solubilized phospholipid bilayers to form lipoproteins that provided substrates for sPLA2. Moreover, SAA sequestered free fatty acids and lysophospholipids to form stable proteolysis-resistant complexes. Unlike albumin, SAA effectively removed free fatty acids under acidic conditions, which characterize inflammation sites. Therefore, SAA solubilized lipid bilayers to generate substrates for sPLA2 and removed its bioactive products. Consequently, SAA and sPLA2 can act synergistically to remove cellular membrane debris from the injured sites, which is a prerequisite for tissue healing. We postulate that removal of lipids and their degradation product...
Human Group IIA Phospholipase A2—Three Decades on from Its Discovery
Molecules
Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Func...
Biology of Secretory Phospholipase A2
Cardiovascular Drugs and Therapy, 2008
Introduction The secretory phospholipase A 2 (sPLA 2) family provides a seemingly endless array of potential biological functions that is only beginning to be appreciated. In humans, this family comprises 9 different members that vary in their tissue distribution, hydrolytic activity, and phospholipid substrate specificity. Through their lipase activity, these enzymes trigger various cell-signaling events to regulate cellular functions, directly kill bacteria, or modulate inflammatory responses. In addition, some sPLA 2 's are high affinity ligands for cellular receptors. Objective This review merely scratches the surface of some of the actions of sPLA 2 s in innate immunity, inflammation, and atherosclerosis. The goal is to provide an overview of recent findings involving sPLA 2 s and to point to potential pathophysiologic mechanisms that may become targets for therapy.