Objective-Abdominal aortic aneurysm (AAA) is a complex vascular disease characterized by matrix degradation and inflammation and is a major cause of mortality in older men. Specific interventions that prevent AAA progression remain to be identified. In this study, we tested the hypothesis that Group X secretory phospholipase A 2 (GX sPLA 2 ), an enzyme implicated in inflammatory processes, mediates AAA.Methods and Results-GX sPLA 2 was detected by immunostaining in human aneurysmal tissue and in angiotensin II (Ang II)-induced AAAs in apolipoprotein E-deficient (apoE −/− ) mice. GX sPLA 2 mRNA was increased significantly (11-fold) in abdominal aortas of apoE −/− mice in response to Ang II infusion. To define the role of GX sPLA 2 in experimental AAAs, apoE −/− and apoE −/− × GX sPLA 2 −/− (GX DKO) mice were infused with Ang II for either 10 (n=7) or 28 (n=24-26) days. Deficiency of GX sPLA 2 significantly reduced the incidence and severity of AAAs, as assessed by ultrasound measurements in vivo of aortic lumens and by computer-assisted morphometric analyses ex vivo of external diameter. Results from gene expression profiling indicated that the expression of specific matrix metalloproteinases and inflammatory mediators was blunted in aortas from GX DKO mice compared to apoE −/− mice after 10-day Ang II infusion. Ang II induction of cyclooxygenase-2, interleukin-6, matrix metalloproteinase (MMP)-2, MMP-13 and MMP-14 was reduced significantly in GX DKO mice compared to apoE −/− mice.

Objective-In vitro data indicate that human LDL modified by Group V secretory phospholipase A 2 (GV sPLA 2 ) is proatherogenic. Consistent with this, gain and loss of function studies demonstrated that GV sPLA 2 promotes atherosclerosis in LDLR Ϫ/Ϫ mice. The current study investigates whether GV sPLA 2 promotes atherosclerotic processes in apoE Ϫ/Ϫ mice. Methods and Results-LDL (dϭ1.019 to 1.063) from apoE Ϫ/Ϫ and LDLR Ϫ/Ϫ mice fed chow or Western diet were hydrolyzed by GV sPLA 2 . Phosphatidylcholine on LDL from LDLR Ϫ/Ϫ mice fed either a chow or Western diet was hydrolyzed to a greater extent (61.1Ϯ0.4% and 45.3Ϯ4.6%) than the corresponding fractions from apoE Ϫ/Ϫ mice (41.7Ϯ3.6% and 39.4Ϯ1.2%). ApoE Ϫ/Ϫ LDL induced macrophage foam cell formation in vitro without modification by GV sPLA 2 , whereas hydrolysis of LDLR Ϫ/Ϫ LDL was a prerequisite for foam cell formation. In contrast to findings in LDLR Ϫ/Ϫ mice, GV sPLA 2 deficiency did not significantly reduce atherosclerosis in apoE Ϫ/Ϫ mice, although collagen content was significantly reduced in lesions of apoE Ϫ/Ϫ mice lacking GV sPLA 2 . Conclusions-The ability of GV sPLA 2 to promote atherosclerotic lipid deposition in apoE Ϫ/Ϫ and LDLR Ϫ/Ϫ mice may be related to its ability to increase the atherogenic potential of LDL from these mice as assessed in vitro. Key Words: sphingomyelin Ⅲ foam cells Ⅲ cholesterol ester Ⅲ atherosclerosis S ecretory phospholipase A 2 (sPLA 2 ) 1 enzymes hydrolyze the fatty acid at the sn-2 position of glycerophospholipids. 1 Ten sPLA 2 isoforms have been described in mammals, and at least 7 of these can be detected in human atherosclerotic lesions. 2 These enzymes have been suggested to promote atherosclerosis through their hydrolyzing activities in the arterial intima. 3-5 GV, GX, and GIII sPLA 2 have been shown to effectively hydrolyze LDL. 6 -9 Our laboratory has shown that GV sPLA 2 hydrolysis of human LDL produces smaller LDL that are susceptible to aggregation, 7 modifications that enhance LDL retention in the vessel wall. In addition, GV sPLA 2 hydrolysis promotes LDL uptake by macrophages through a pathway that is independent of macrophage scavenger receptors and that involves cell surface proteoglycans. 10 Consistent with in vitro findings, overexpression of GV sPLA 2 in bone marrow-derived cells results in increased atherosclerosis in LDLR Ϫ/Ϫ mice, whereas deficiency of the enzyme results in reduced atherosclerosis. 11 However, several considerations led us to question whether GV sPLA 2 plays a major role in atherosclerotic lipid deposition in apoE Ϫ/Ϫ mice. First, in vitro studies have shown that LDL isolated from apoE Ϫ/Ϫ mice are oxidatively modified and hence induce macrophage foam cell formation in a CD36-dependent manner without the requirement for further modification. 12 Secondly, lipoprotein phospholipid (PL) content is altered in apoE Ϫ/Ϫ mice, such that the SM to PC ratio is relatively high because of increased SM production and decreased SM degradation. 13 Because previous in vitro data demonstrate that G...

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Moderate protein and nonfat dairy intake within an energy-reduced diet (ERD) may contribute to health benefits achieved with body weight (BW) loss. The current study examined the effectiveness of a weight-loss/weight-loss maintenance intervention using an ERD with moderate dietary protein (30% of kcals) and increased nonfat dairy intake (4–5 svg/d), including yogurt (INT group) and daily walking compared to an ERD with standard protein (16–17% of kcals) and standard nonfat dairy intake (3 svg/d) (COM group) with daily walking. A randomized comparative trial with 104 healthy premenopausal women with overweight/obesity was conducted in a university setting. Women were randomized to INT group or COM group. Anthropometric measurements, as well as dietary intake, selected vital signs, resting energy expenditure, blood lipids, glucose, insulin, and selected adipose-derived hormones were measured at baseline, and weeks 2, 12, and 24. Targets for dietary protein and nonfat dairy intake, while initially achieved, were not sustained in the INT group. There were no significant effects of diet group on anthropometric measurements. Women in the INT group and COM group, respectively, reduced BW (−4.9 ± 3.2 and −4.3 ± 3.3 kg, P < 0.001) and fat mass (−3.0 ± 2.2 and −2.3 ± 2.3 kg, P < 0.001) during the 12-week weight-loss phase and maintained these losses at 24 weeks. Both groups experienced significant decreases in body mass index, fat-free soft tissue mass, body fat percentage, waist and hip circumferences and serum triglycerides, total cholesterol, and leptin (all P < 0.001). Healthy premenopausal women with excess adiposity effectively lost BW and fat mass and improved some metabolic risk factors following an ERD with approximately 20% protein and 3 svg/d of nonfat dairy intake.

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