Specific Secretory Phospholipase A2 Isozymes Promote Aneurysm Formation

University Of Kentucky, Lexington KY

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Abstract

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