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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 ...

We have reported that liver-specific deletion of IGF-I in mice (LI-IGF-I-/-) results in decreased circulating IGF-I and increased GH levels. In the present study, we determined how elimination of hepatic IGF-I modifies the hypothalamic-pituitary GH axis to enhance GH secretion. The pituitary mRNA levels of GH releasing factor (GHRF) receptor and GH secretagogue (GHS) receptor were increased in LI-IGF-I-/- mice, and in line with this, their GH response to ip injections of GHRF and GHS was increased. Expression of mRNA for pituitary somatostatin receptors, hypothalamic GHRF, somatostatin, and neuropeptide Y was not altered in LI-IGF-I-/- mice, whereas hypothalamic IGF-I expression was increased. Changes in hepatic expression of major urinary protein and the PRL receptor in male LI-IGF-I-/- mice indicated an altered GH release pattern most consistent with enhanced GH trough levels. Liver weight was enhanced in LI-IGF-I-/- mice of both genders. In conclusion, loss of liver-derived IGF-I enhances GH release by increasing expression of pituitary GHRF and GHS receptors. The enhanced GH release in turn affects several liver parameters, in line with the existence of a pituitary-liver axis.

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