Ultrastructural Localization of Secretory Type II Phospholipase A ₂ in Atherosclerotic and Nonatherosclerotic Regions of Human Arteries

Abstract

Abstract-We recently reported on the immunolocalization of type II secretory nonpancreatic phospholipase A 2 (snpPLA 2 ) in human atherosclerotic lesions. In the present study, we present data on the distribution and ultrastructural localization of snpPLA 2 in adjacent nonatherosclerotic and atherosclerotic regions of human arteries. Electron microscopy (EM) of immunogold labeling techniques with a monoclonal antibody was used to analyze arterial tissue. The human specimens analyzed were obtained from autopsy and surgery cases. The results with EM showed a stronger snpPLA 2 immunoreactivity in regions of arteries with atherosclerotic lesions than in regions without lesions from the same individual. snpPLA 2 immunoreactivity was stronger in the arterial intima of atherosclerotic than of nonatherosclerotic tissue. EM-immunogold examination revealed that the majority of snpPLA 2 was localized along the extracellular matrix, associated with collagen fibers and other extracellular matrix structures. Intracellular snpPLA 2 was observed in electron-dense vesicles in intimal cells. snpPLA 2 was also found in contact with large, extracellular lipid droplets. These results support the hypothesis that extracellular snpPLA 2 is localized at sites where it may hydrolyze phospholipids from lipoproteins and lipid aggregates retained in the extracellular matrix of the arterial wall. This may be a mechanism for in situ release of proinflammatory lipids, free fatty acids, and lysophosphatidylcholine in regions of apolipoprotein B accumulation, which are abundant in atherosclerotic lesions. (Arterioscler Thromb Vasc Biol. 1998;18:519-525.)

Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I

“…Pathologic studies have indicated substantial evidence for inflammation within the atherosclerotic plaque (60). Group IIA sPLA 2 is synthesized constitutively within the vessel wall by vascular smooth muscle cells (61,62) and is associated with heparan sulfate proteoglycans of the extracellular matrix (63,64). Administration of heparin to humans results in a marked increase in plasma PLA 2 activity and immunoreactive group IIA sPLA 2 (65), suggesting that it is present in the vessel wall under physiologic conditions.…”

“…Administration of heparin to humans results in a marked increase in plasma PLA 2 activity and immunoreactive group IIA sPLA 2 (65), suggesting that it is present in the vessel wall under physiologic conditions. Cytokines up-regulate VSMC expression of group IIA sPLA 2 in vitro (61) and in vivo (62), and sPLA 2 is present in markedly increased amounts within the atherosclerotic plaque (63,64,66). Transgenic overexpression of sPLA 2 in mice results in increased atherosclerosis (67).…”

Mitogenic Effect of Lipoproteins on Human Vascular Smooth Muscle Cells: The Impact of Hydrolysis by gr II A Phospholipase A2

“…It was found, however, that HDL localizes in the arterial wall in the cellular compartment and along with LDL is internalized by the macrophages and by VSMC, especially in the atherosclerotic plaques (Robenek and Severs, 1993). Since sPLA 2 co-localizes in the same areas (Hurt-Camejo et al, 1997; Romano et al, 1998;Sartipy et al, 1998), it most probably is capable of interacting with lipoproteins in situ.…”

“…sPLA 2 is present in the media in normal and more so in atherosclerotic arteries specifically colocalizing with VSMC (Hurt-Camejo et al, 1997;Romano et al, 1998). In the atherosclerotic wall, sPLA 2 was detected both extracellularly in the lipid core, binding avidly to the proteoglycans synthesized by VSMC (Sartipy et al, 1998), and intracellularly in the macrophages (Hurt-Camejo et al, 1997;Romano et al, 1998). We found concentrations of sPLA 2 exceeding 50 ng/mg wet weight in the atherosclerotic arterial walls (Pruzanski et al, unpublished).…”

“…It has been shown that in atherosclerosis, lipoproteins and sPLA 2 are colocalized in the vascular wall, mainly in the domain of the smooth muscle cells (Hurt-Camejo et al, 1997;Robenek and Severs, 1993;Romano et al, 1998;Sartipy et al, 1998). Thus, it is of significant interest that in some diseases such as systemic lupus erythematosus, in which SAA and sPLA 2 are co-overexpressed for long periods (de Beer et al, 1982;Pruzanski et al, 1994), accelerated atherosclerosis takes place (Bruce et al, 1998;Urowitz and Gladman, 1999).…”