Abstract-Secretory phospholipase A 2 (PLA 2 ) can be proatherogenic both in the circulation and in the arterial wall. In blood plasma, PLA 2 can modify the circulating lipoproteins and so induce formation of small dense LDL particles, which are associated with increased risk for cardiovascular disease. In the arterial wall, PLA 2 can hydrolyze lipoproteins. The PLA 2 -modified lipoproteins bind tightly to extracellular proteoglycans, which may lead to their enhanced retention in the arterial wall. The modified lipoproteins may also aggregate and fuse, which can lead to accumulation of their lipids within the extracellular matrix. The PLA 2 -modified particles are more susceptible to further modifications by other enzymes and agents and can be taken up by macrophages, leading to accumulation of intracellular lipids. In addition, lysophospholipids and free fatty acids, the hydrolysis products of PLA 2 , promote atherogenesis. Thus, these lipid mediators can be carried, either by the PLA 2 -modified lipoproteins themselves or by albumin, into the arterial cells, which then undergo functional alterations. This may, in turn, lead to specific changes in the extracellular matrix, which increase the retention and accumulation of lipoproteins within the matrix. In the present article, we discuss the possible actions of PLA 2 enzymes, especially PLA 2 -IIA, in the arterial wall during atherogenesis. (Circ Res. 2001;89:298-304.)

This article briefly summarizes, within the context of a brief review of the relevant literature, the outcome of our recent rat microdialysis studies on (1) the relative importance of serotonin (5-HT)1A versus 5-HT1B autoreceptors in the mechanism of action of 5-HT reuptake blocking agents, including putative regional differences in this regard, and (2) autoreceptor responsiveness following chronic SSRI administration. First, our data are consistent with the primacy of 5-HT1A autoreceptors in restraining the elevation of 5-HT levels induced by SSRIs, whereas nerve terminal 5-HT1B autoreceptors appear to have an accessory role in this regard. Second, there is an important interplay between cell body and nerve terminal 5-HT autoreceptors, and recent findings suggest that this interplay may potentially be exploited to obtain regionally preferential effects on 5-HT neurotransmission in the central nervous system, even upon systemic drug administration. In particular, emerging data suggest that somatodendritic 5-HT1A autoreceptor- and nerve terminal 5-HT1B autoreceptor-mediated feedback may be relatively more important in the control of 5-HT output in dorsal raphe-frontal cortex and median raphe-dorsal hippocampus systems, respectively. Third, 5-HT autoreceptors evidently retain the capability to limit the 5-HT transmission-promoting effect of SSRIs after chronic treatment. Thus, although the responsiveness of these sites is probably somewhat reduced, residual autoreceptor capacity still remains an effective restraint on large increases in extracellular 5-HT, even after prolonged treatment. If a further increase in extracellular 5-HT is crucial to the remission of depression in patients responding only partially to prolonged administration of antidepressants, then sustained adjunctive treatment with autoreceptor-blocking drugs may consequently prove useful in the long term.

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Objective-To study the distribution of group V secretory phospholipase A 2 (sPLA 2 ) in human and mouse lesions and compare its expression by human vascular cells, its activity toward lipoproteins, and the interaction with arterial proteoglycans (proteoglycans) with those of sPLA 2 -IIA. In addition, we also investigated the effect of a Western diet and lipopolysaccharide challenge on the aortic expression of these enzymes in mouse models. Methods and Results-Immunohistochemistry showed sPLA 2 -V in human and mouse lesions to be associated with smooth muscle cells and also surrounding foam cells in lipid core areas. mRNA of the enzyme was expressed in human lesions and human vascular cells, supporting the immunohistochemistry data. sPLA 2 -V but not sPLA 2 -IIA was active on lipoproteins in human serum. The association with proteoglycans enhanced 2-to 3-fold sPLA 2 -V activity toward low-density lipoproteins but not that of the group IIA enzyme. Experiments in mouse models showed that treatment with a Western diet induced expression of sPLA 2 -V but not that of sPLA 2 -IIA in aorta. On the other hand, lipopolysaccharide-induced acute inflammation augmented the expression of sPLA 2 -IIA but not that of sPLA 2 -V. Key Words: phospholipase Ⅲ atherogenesis Ⅲ inflammation Ⅲ lipoprotein-retention Ⅲ proteoglycans D uring atherosclerosis development, there is a progressive decrease of the lesion phospholipid content and enrichment in cholesterol. 1 Furthermore, apolipoprotein B (apoB) lipoproteins isolated from human and rabbit lesions contain less phosphatidylcholine (PC) and more sphingomyelin than circulating lipoproteins. 2,3 Therefore, lipoproteins trapped in the intima appear to be hydrolyzed by secretory phospholipases. 4 These enzymes may contribute to atherosclerosis by hydrolysis of low-density lipoprotein (LDL) phospholipids that induce fusion and increase binding of cholesterol-rich particles to intima proteoglycans, triggering further modifications. [5][6][7][8] In addition, phospholipase(s) A 2 contribute to local release of lyso-phospholipids and nonesterified fatty acids, which have proinflammatory properties in arterial cells. 9 -12 Conclusions-These See page 1421Secretory phospholipase A 2 (sPLA 2 ) group IIA is present in human atherosclerotic lesions, and experimental and clinical evidence suggest its involvement in atherosclerosis and cardiovascular disease. 13-17 sPLA 2 -IIA and the more recently cloned sPLA 2 -V are members of a family of enzymes that hydrolyze the fatty acids at the sn-2 position of glycerophospholipids. Both enzymes have low molecular weight (14 kDa), are histidine and calcium dependent, rich in disulfide bonds, are basic, and share structure similarities. 18 Several of these properties stabilize and enhance their activity in the extracellular milieu. The genes of sPLA 2 -IIA and sPLA 2 -V enzymes are located at close positions in homologous regions in mouse chromosome 4 and human chromosome 1 and share the same promoter. 19 This region was identified as an atherosclerosis ...