Biological effects of secretory phospholipase A₂ group IIA on lipoproteins and in atherogenesis

Abstract

Secretory phospholipase A(2) group IIA(sPLA(2) IIA) can be produced and secreted by various cell types either constitutionally or as an acute-phase reactant upon stimulation by proinflammatory cytokines. The enzyme prefers phosphatidylethanolamine and phosphatidylserine as substrates. One important biological function may be the hydrolytic destruction of bacterial membranes. It has been demonstrated, however, that sPLA(2) can also hydrolyse the phospholipid monolayers of high density lipoprotein (HDL) and low density lipoprotein (LDL) in vitro. Secretory phospholipase A(2)-modified LDL show increased affinity to glycosaminoglycans and proteoglycans, a tendency to aggregate, and an enhanced ability to deliver cholesterol to cells. Incubation of cultured macrophages with PLA(2)-treated LDL and HDL is associated with increased intracellular lipid accumulation, resulting in the formation of foam cells. Elevated sPLA(2)(IIA) activity in blood serum leads to an increased clearance of serum cholesterol. Secretory phospholipase A(2)(IIA) can also be detected in the intima, adventitia and media of the atherosclerotic wall not only in developed lesions but also in very early stages of atherosclerosis. The presence of DNA of Chlamydia pneumoniae, herpes simplex virus, and cytomegalovirus was found to be associated with sPLA(2)(IIA) expression and other signs of local inflammation. Thus, sPLA(2)(IIA) appears to be one important link between the lipid and the inflammation hypothesis of atherosclerosis.

Biomarkers of Vascular Disease Linking Inflammation to Endothelial Activation

“…Detected in human atherosclerotic plaques using immunohistochemical staining, but not in normal arteries without signs of ongoing inflammatory reactions, its biological roles may include antibiotic function, contribution to the removal of injured or apoptotic cells, and enhancing the clearance of cholesterol from the bloodstream. [61][62][63] However, within plaques, it can play a proatherogenic role. Like Lp-PLA 2 , sPLA 2 is able to catalyze the sn-2 ester bonds of glycerophospholipids resulting in the generation of lysophospholipids, such as lysoPC, which may trigger inflammatory cellular processes as discussed above.…”

“…Like Lp-PLA 2 , sPLA 2 is able to catalyze the sn-2 ester bonds of glycerophospholipids resulting in the generation of lysophospholipids, such as lysoPC, which may trigger inflammatory cellular processes as discussed above. 63 The cellular components of the plaque, SMCs, endothelial cells, mast cells, and macrophages, possess the ability to synthesize sPLA 2 . 63 Secretion of sPLA 2 is induced by proinflammatory compounds within the atherosclerotic environment such as IL-1, IL-6, TNF-␣, interferon-␥, and oxLDL, enhancing plaque formation.…”

“…63 The cellular components of the plaque, SMCs, endothelial cells, mast cells, and macrophages, possess the ability to synthesize sPLA 2 . 63 Secretion of sPLA 2 is induced by proinflammatory compounds within the atherosclerotic environment such as IL-1, IL-6, TNF-␣, interferon-␥, and oxLDL, enhancing plaque formation. 63,64 Plaque formation is further enhanced via the role of sPLA 2 in increasing intracellular lipid accumulation within macrophages leading to foam-cell formation.…”

“…63 Secretion of sPLA 2 is induced by proinflammatory compounds within the atherosclerotic environment such as IL-1, IL-6, TNF-␣, interferon-␥, and oxLDL, enhancing plaque formation. 63,64 Plaque formation is further enhanced via the role of sPLA 2 in increasing intracellular lipid accumulation within macrophages leading to foam-cell formation. 63 sPLA 2 activity has been implicated in promoting monocyte chemoattractant protein-1 secretion by monocytes as well as inducing the surface display of functional CD40 on monocytic cells.…”

“…63,64 Plaque formation is further enhanced via the role of sPLA 2 in increasing intracellular lipid accumulation within macrophages leading to foam-cell formation. 63 sPLA 2 activity has been implicated in promoting monocyte chemoattractant protein-1 secretion by monocytes as well as inducing the surface display of functional CD40 on monocytic cells. 65,66 Thus, sPLA 2 may serve as a link between the lipid and the inflammation hypothesis of atherosclerosis.…”