Abdominal aortic aneurysm (AAA) is a major medical concern due to the increasing prevalence and high mortality rate. There is an urgent need for alternative therapeutic strategies for AAA, since current treatment is limited to open or endovascular surgery, for which only 10% of the patients are eligible. The clinical detection and quantitation of nitric oxide-dependent fatty acid nitration products (nitroalkenes) among other fatty acids species, has sparked the interest on novel anti-inflammatory lipids targeting the cardiovascular system. Recent improvements in the methodology of detection and advances in metabolomics and lipidomics strategies have more precisely determined the abundance of the fatty acid nitration milieu. These novel tools have identified conjugated linoleic acid (CLA) as th preferential substrate for fatty acid nitration in humans. Most importantly, it has been determined that CLA nitration is readily bioavailable in humans and experimental models upon oral delivery of CLA and inorganic nitrite (NO2). However, whether parenteral nitro-CLA formation has functional benefits and salutary properties in the cardiovascular system remains to be explored. Herein, it is shown that nitro-CLA formation readily translates into anti-inflammatory mechanisms in the vasculature. In an experimental model of angiotensin II-induced AAA, oral delivery of a combination of CLA and nitrite efficiently abolishes the maximal intraluminal diameter of the abdominal aorta, and significantly reduces the incidence of aortic ruptures. Oral delivery of CLA and nitrite yields therapeutic concentrations of nitro-CLA in the nanomolar range sufficient to reduce elastin degradation, adventitial fibroblast proliferation and migration. Furthermore, endogenous nitro-CLA inhibits macrophage infiltration at the interphase of perivascular adipose tissue and adventitial layer. Finally, nitro-CLA serves as an agonist of the PPAR? nuclear receptor, a key transcription factor involved in the regulation of vascular proliferation, and matrix metalloproteinase (MMP) production. Based on this evidence, this proposed project will test the central hypothesis that enhancing the endogenous production of nitro-conjugated linoleic acid protects against aortic aneurysm by reducing adventitial fibroblast migration, and macrophage infiltration into the periaortic vasculature. Specifically, we will 1). Determine the endogenous generation of nitro-CLA by an oral therapeutic approach to protect against aortic aneurysm; 2). Define macrophage PPAR? as a key factor mediating nitro-CLA reduction of aortic aneurysm formation; 3). Determine that nitro-CLA-mediated perivascular PPAR? activation inhibits aortic aneurysm.

Public Health Relevance

Abdominal aortic aneurysm (AAA) is a major medical concern due to the increasing prevalence and high mortality rate. There is an urgent need for alternative therapeutic strategies for AAA, since current treatment is limited to surgery, for which only 10% of the patients are eligible. The proposed project is relevant for the public health because it wil establish the feasibility of a novel pharmacological approach to directly target AAA using orally bioavailable nitrated conjugated linoleic acid.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068878-18
Application #
9397555
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chen, Jue
Project Start
2002-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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