# The role of TFEB in aortic aneurysms

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2021 · $538,002

## Abstract

ABSTRACT
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 lysosomal
biogenesis and autophagy. However, the role of TFEB in VSMC functions and AAA formation remain to be
explored. We demonstrated that TFEB inhibits apoptosis, MMP2/9 activity and inflammation 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 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 in an H148-dependent fashion 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 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.
We will test our working sub-hypothesis that VSMC TFEB protects against AAA formation 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 formation in vivo. The working sub-
hypothesis is that endogenous production of nitro-CLA protects against AAA formation through activation of
VSMC TFEB. In summary, we will characterize the protective role of TFEB in AAA formation 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.

## Key facts

- **NIH application ID:** 10199015
- **Project number:** 5R01HL145176-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Yanbo Fan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $538,002
- **Award type:** 5
- **Project period:** 2020-06-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199015

## Citation

> US National Institutes of Health, RePORTER application 10199015, The role of TFEB in aortic aneurysms (5R01HL145176-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10199015. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*