Abdominal aortic aneurysms (AAA) formation and subsequent aortic rupture can lead to sudden death and is a significant clinical problem with no currently known medical treatments available. Our recent studies have characterized a protective role of specialized pro-resolving mediators (SPMs) that are ?-3-fatty acid lipid derivatives i.e. Resolvin (Rv)D1 that effectively attenuates AAA formation via modulating the M1/M2 macrophage polarization. In this proposal, we will delineate the phenotype and mechanisms of bioactive isoforms of SPMs i.e. Resolvins (RvD1), Maresins (MaR-1), Protectins (PD-1) and Lipoxins (LxB4) that can lead to resolution of aortic aneurysm formation and prevent aortic rupture. First, we will measure SPMs in human AAA patients and aortic tissue from murine experimental AAA model via electrospray tandem mass spectrometry coupled to liquid chromatography (LC/ESI-MS/MS), which is a sensitive analytical methodology for the qualitative and quantitative analysis of lipid mediators. Then, we will characterize the synergistic response of these SPM bioactive isoforms in our murine AAA and aortic rupture models. Finally, we will delineate the specific mechanisms of the bioactive isoforms of SPMs i.e. RvD1, MaR-1, PD-1 and LxB4 using in vivo and in vitro studies. Our preliminary data demonstrates that treatment with MaR-1 can prevent the progression of aneurysm formation that is associated with aortic smooth muscle cell (SMC)-TGF-?1 signaling. Recent reports suggest that oxidized mitochondrial (mt) DNA acts as a damage associated pattern molecule to form NETs, but it remains to be characterized in AAAs. Therefore, the role of MaR-1 in promoting macrophage- dependent efferocytosis (the process of uptake of apoptotic/necrotic neutrophils) associated with NET formation will also be elucidated in human AAA tissue as well as experimental murine models. Moreover, we will quantify SPM-related G-protein coupled receptors (GPCR) i.e. (ALX/FPR2, GPR32, GPR18, and ChemR23) signaling in AAA. Specifically, RvD1/FPR2 signaling via AMP-activated protein kinase (AMPK) to regulate pro-inflammatory macrophage secretion of GM-CSF and HMGB1 will be deciphered in AAA formation. Therefore, we will characterize the unique ability of SPMs to treat preformed aneurysms and prevent aortic rupture by modulating RvD1-FPR2 signaling, mtDNA-dependent NETosis, promoting efferocytosis and modulating SMC-dependent TGF-?1 signaling. This multi-faceted targeted approach of specific SPM isoforms demonstrate a clinically applicable therapeutic strategy for treatment of chronic aortic inflammation and vascular remodeling by targeting macrophages, neutrophils and smooth muscle cells. Our scientific premise is to perform an in-depth analysis of the roles of these pro-resolving lipid derived mediators in the chronic models of aneurysm formation. Importantly, we will test the rigor and reproducibility of these animal studies to determine whether these transitions occur in human tissue using ex vivo aortic explants.
Abdominal aortic aneurysms (AAA) and subsequent aortic rupture can lead to sudden death and are a significant clinical problem with increasing prevalence and no known medical treatment. Our goal with the present proposal is to identify whether the specialized pro-resolving lipid derived mediators i.e. Resolvins, Maresins, Protectins and Lipoxins can decrease AAA formation and prevent aortic rupture in our newly developed chronic inflammatory mouse model of aneurysm formation and aortic rupture. Importantly, the clinical translation of the experimental studies will be enhanced, as we will determine whether these treatment options are relevant in human AAA by using ex vivo and co-culture techniques with patient samples.
