# Alleviation of chemotherapy-induced cardiovascular toxicity

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2024 · $726,408

## Abstract

ABSTRACT
Many cancer drugs increase cardiovascular (CV) events, including hypertension, thrombosis, and
cardiomyopathy. Damaged endothelial cells (ECs) caused by chemotherapy can trigger the development and
progression of cardiovascular disease (CVD). ECs represent a critical target for improving the management of
chemotherapy-induced CV toxicity. The lysosomal pathway is critical to maintaining EC homeostasis.
However, the role of lysosomes in chemotherapy-induced EC dysfunction and whether rescuing lysosomal
function is a potential strategy to treat CV toxicity remain to be fully explored. Our preliminary data suggest that
the chemotherapeutic drug doxorubicin (DOX) impairs lysosomal function in ECs. TFEB is a master regulator
of autophagy and lysosome biogenesis. Our previous studies demonstrated that endothelial TFEB protects
against atherosclerosis, increases glucose uptake, and improves blood flow recovery after ischemic injury,
underscoring the critical role of EC TFEB in regulating CV hemostasis. Our preliminary data suggest that EC-
TFEB transgene regulates DOX-induced cardiac dysfunction in mice. TFEB controls lysosomal malfunction,
apoptosis, oxidative stress, and inflammation induced by DOX in human ECs. Our RNA-seq data identified
multiple lysosomal-associated pathways in ECs treated with DOX. Based on the solid rationale and preliminary
data, we will define the role of endothelial TFEB in CV dysfunction induced by cancer treatment. By taking
advantage of our EC-specific transgenic (Tg) and knockout (KO) mouse models and the combined expertise of
the assembled team, three Specific Aims are proposed. Specific Aim 1: Define the role of endothelial TFEB in
cancer therapy-induced EC dysfunction and EC-cardiomyocyte interaction in vitro; Specific Aim 2: Define the
role of EC TFEB in cancer therapy-induced CV toxicity in vivo; Specific Aim 3: Elucidate the mechanisms
mediating the effects of EC TFEB on cancer therapy-induced cardiac dysfunction in vivo. Understanding
endothelial TFEB’s role and underlying mechanisms in cancer therapy-induced CV toxicity would set a
profound foundation to define endothelial TFEB as a potential therapeutic target to treat CV complications
caused by cancer therapy.

## Key facts

- **NIH application ID:** 10979977
- **Project number:** 1R01HL171495-01A1
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Wa Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $726,408
- **Award type:** 1
- **Project period:** 2024-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979977

## Citation

> US National Institutes of Health, RePORTER application 10979977, Alleviation of chemotherapy-induced cardiovascular toxicity (1R01HL171495-01A1). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10979977. Licensed CC0.

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