Secretory phospholipase A2 enzymes (sPLA2's), in particular the Group HA, Group V, and Group X subtypes, have been implicated in a wide variety of inflammatory diseases. We provide evidence that sPLA2s play a role in promoting abdominal aortic aneurysm (AAA) formation in a mouse model of this vascular disease. An sPLA2 inhibitor of broad specificity profoundly reduces both the incidence and severity of Angiotensin II (Angll)-induced AAAs in apoE-/- mice. Additionallly, transgenic mice expressing human Group IIA sPLA2 have increased susceptibility to Angll-induced AAAs compared to non-transgenic mice. The central hypothesis of this proposal is that Group IIA, Group V, and/or Group X sPLA2 expressed by macrophages infiltrating into the vessel wall accelerate AAA formation by promoting the localized release of inflammatory prostanoids. This hypothesis is based on published data and our own preliminary findings that: a) macrophage infiltration into the medial layer of the abdominal aorta is an early event in AAAs;b) Group V and Group X sPLA2 protein are present in AAAs in apoE-/- mice c) the aortic expression of Group V and Group X sPLA2 mRNA is increased in apoE-/- mice infused with Angll;d) these isozymes are expressed by macrophages;e) these isozymes have been implicated in cyclooxygenase 2 (COX-2)-dependent prostanoid production;and f) mice treated with a COX-2-selective inhibitor have significantly reduced AAAs in response to chronic Angll infusion. To test this hypothesis, we propose to identitify specific sPLA2(s) mediating AAA progression, and define the relative contribution of leukocyte expression of these sPLA2 isozymes in its pathogenic effect (Specific Aim 1);define the relative contribution of systemic versus leukocyte-expressed Group IIA sPLA2 in mediating Angll-induced AAAs (Specific Aim 2);and determine whether the pathogenic effect of sPLA2 is dependent on COX-2 activity (Specific Aim 3). These studies hold the potential to identify a new target for AAA intervention.
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