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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL080100-05
Application #
8050624
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$360,000
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Davis, Frank M; Rateri, Debra L; Daugherty, Alan (2015) Abdominal aortic aneurysm: novel mechanisms and therapies. Curr Opin Cardiol 30:566-73
Liu, Jing; Lu, Hong; Howatt, Deborah A et al. (2015) Associations of ApoAI and ApoB-containing lipoproteins with AngII-induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol 35:1826-34
Webb, Nancy R; De Beer, Maria C; Wroblewski, Joanne M et al. (2015) Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE-/- Mice From Angiotensin II-Induced Abdominal Aortic Aneurysm Formation. Arterioscler Thromb Vasc Biol 35:1156-65
Blomkalns, Andra L; Gavrila, Daniel; Thomas, Manesh et al. (2013) CD14 directs adventitial macrophage precursor recruitment: role in early abdominal aortic aneurysm formation. J Am Heart Assoc 2:e000065
Subramanian, Venkateswaran; Moorleghen, Jessica J; Balakrishnan, Anju et al. (2013) Calpain-2 compensation promotes angiotensin II-induced ascending and abdominal aortic aneurysms in calpain-1 deficient mice. PLoS One 8:e72214
Lu, Hong; Rateri, Debra L; Bruemmer, Dennis et al. (2012) Involvement of the renin-angiotensin system in abdominal and thoracic aortic aneurysms. Clin Sci (Lond) 123:531-43
Wang, Shaoping; Subramanian, Venkateswaran; Lu, Hong et al. (2012) Deficiency of receptor-associated protein attenuates angiotensin II-induced atherosclerosis in hypercholesterolemic mice without influencing abdominal aortic aneurysms. Atherosclerosis 220:375-80
Xie, Xiaojie; Lu, Hong; Moorleghen, Jessica J et al. (2012) Doxycycline does not influence established abdominal aortic aneurysms in angiotensin II-infused mice. PLoS One 7:e46411
Rateri, Debra L; Moorleghen, Jessica J; Knight, Victoria et al. (2012) Depletion of endothelial or smooth muscle cell-specific angiotensin II type 1a receptors does not influence aortic aneurysms or atherosclerosis in LDL receptor deficient mice. PLoS One 7:e51483
Subramanian, Venkateswaran; Golledge, Jonathan; Heywood, Elizabeth B et al. (2012) Regulation of peroxisome proliferator-activated receptor-? by angiotensin II via transforming growth factor-?1-activated p38 mitogen-activated protein kinase in aortic smooth muscle cells. Arterioscler Thromb Vasc Biol 32:397-405

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