# Transcription Factor-EB and Postischemic Angiogenesis

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $440,534

## Abstract

ABSTRACT
Peripheral arterial disease (PAD) is highly prevalent and is increasingly recognized as a major contributor to
the cardiovascular disease (CVD) and public health burden. Critical limb ischemia (CLI) is one of the most
advanced PAD. To date, beside endovascular or surgical treatment, few therapeutic alternatives to restore the
blood flow in ischemic tissues are available. Therefore, it would be of high significance to identify novel
strategies to treat ischemic vascular injury in vivo. Transcription factor-EB (TFEB) is a crucial regulator of
lysosomal biogenesis and autophagy.
However, the functions of TFEB in vascular disease remain to be
explored.
The clinical detection and quantitation of nitric oxide (NO)-dependent fatty acid nitration products
(nitroalkenes), has sparked the interest on novel anti-inflammatory lipids. Free and esterified nitro-fatty acid
derivatives have been detected in human and animal plasma in the nanomolar range and shown to have
profound implications in the prevention of diverse pathophysiological aspects of CVDs. Significant advances in
metabolomics and lipidomics strategies identified conjugated linoleic acid (CLA) as the preferential substrate
for fatty acid nitration in humans. Herein, we show that nitro-conjugated linoleic acid (nitro-CLA) formation
readily translates into protective mechanisms in the vasculature. Our preliminary data indicate that nitro-CLA
enhances autophagy through TFEB in endothelial cells (ECs). Endothelial TFEB significantly increases
postischemic angiogenesis in vivo. Finally, nitro-CLA regulates autophagy and tube formation in a TFEB-
dependent manner. Based on this evidence, the project will test the central hypothesis that enhancing the
endogenous production of nitro-CLA protects against ischemic vascular injury by promoting TFEB-
mediated autophagy leading to enhanced postischemic angiogenesis. Two Specific Aims are proposed.
Aim 1: Establish that endothelial TFEB is essential for nitro-CLA-dependent protective autophagy and
proangiogenic phenotype in vitro. This will be addressed by gain- and loss-of-function approaches in cultured
primary ECs in the presence of nitro-CLA treatment. Aim 2: Establish that endogenous nitro-CLA protects from
ischemic vascular injury in vivo through endothelial TFEB. An oral therapeutic strategy to promote endogenous
nitro-CLA formation will be established. Unique EC-selective TFEB transgenic and knockout mice will be used
to establish that TFEB function is required for nitro-CLA-promoting blood flow recovery in vivo. It is expected
that with this proposal we will better define the essential role of TFEB in nitro-CLA-regulated EC proangiogenic
phenotype and postischemic angiogenesis, and establish oral bioavailability of nitro-CLA as a novel
therapeutic strategy against ischemic vascular injury. This mechanistic research will set a solid foundation for
clinical utilization of nitro-CLA and lead to a major breakthrough for treating or/and preventing...

## Key facts

- **NIH application ID:** 10138366
- **Project number:** 7R01HL138094-04
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Yanbo Fan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,534
- **Award type:** 7
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138366

## Citation

> US National Institutes of Health, RePORTER application 10138366, Transcription Factor-EB and Postischemic Angiogenesis (7R01HL138094-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10138366. Licensed CC0.

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