Group X secretory phospholipase A2 augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice

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 ^-/- x 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. Conclusion: GX sPLA ₂ promotes Ang II-induced pathological responses leading to AAA formation.