Abdominal Aortic aneurysm (AAA) results in very high mortality upon rupture. To date, besides surgical intervention ?with only 10% of patients eligible-, no alternative therapeutic approaches are available. Therefore, it would be of high significance to identify novel strategies to effectively treat or prevent AAA in vivo. Vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular wall integrity and function and VSMC homeostasis is disrupted in AAA. Transcription factor-EB (TFEB) is a ?master? regulator of autophagy and lysosomal biogenesis. However, the role of TFEB in VSMC functions and AAA remain to be explored. We demonstrated that TFEB inhibits apoptosis, inflammation and MMP2/9 activity in VSMCs. VSMC specific TFEB knockout (KO) significantly aggravates vascular wall matrix degradation in a mouse AAA model. Nitroalkene derivatives of fatty acids such as oleic (OA-NO2) and linoleic acid (LNO2) have profound protective effects against cardiovascular and metabolic diseases. Conjugated linoleic acid (CLA) was identified as the preferential and major nitrated endogenous fatty acid and is readily bioavailable in humans and experimental models upon oral delivery of CLA and inorganic nitrite (NO2), making it an attractive intervention for CVD. We found that nitro-CLA protects against AAA formation and progression in the Ang II-induced AAA mouse model and inhibits VSMC inflammation and apoptosis in a TFEB-dependent manner. It also promotes TFEB nuclear translocation in vitro suggesting that TFEB is a direct target of nitro-CLA. Based on these evidences, we will test the central hypothesis that activation of TFEB by enhancing the endogenous production of nitro-CLA protects against AAA formation and progression through inhibition of VSMC dysfunction. By taking advantage of our unique animal models generated specifically for these studies and the combined expertise of the assembled team, we propose 3 aims.
Aim 1 : Characterize the protective role of VSMC TFEB in AAA formation and progression. We will test our working sub-hypothesis that VSMC TFEB protects against AAA through inhibition of VSMC dysfunction.
Aim 2 : Determine that activation of TFEB by nitro-CLA inhibits VSMC dysfunction in vitro. The working sub-hypothesis is that nitro-CLA prevents VSMC dysfunction in a TFEB- dependent manner.
Aim 3 : Define TFEB as a novel therapeutic target for nitro-CLA inhibition of AAA in vivo. The working sub-hypothesis is that endogenous production of nitro-CLA protects against AAA through activation of VSMC TFEB. In summary, we will characterize the protective role of TFEB in AAA and establish nitro-CLA as a novel therapeutic strategy against AAA by targeting VSMC TFEB. This mechanistic research will set a solid foundation for rapid translation into clinical utilization of nitro-CLA and may lead to a breakthrough for treatment or/and prevention of AAA.

Public Health Relevance

Abdominal Aortic aneurysm (AAA) is a life-threatening vascular disease and no alternative therapeutic approaches are available. The successful implementation of this proposal will define TEFB as a novel target of nitro-CLA and establish the feasibility for oral delivery of nitrite and CLA for physiological production of endogenous nitro-CLA as a novel pharmacological approach in prevention and/or treatment of AAA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL145176-01A1
Application #
9818420
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Tolunay, Eser
Project Start
2019-06-03
Project End
2023-05-31
Budget Start
2019-06-03
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
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