# Cellular Senescence: A Novel Mechanism of Doxorubicin-Induced Cardiotoxicity

> **NIH NIH K01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $118,382

## Abstract

Project Summary
Traditionally, cardiotoxic effects in patients undergoing anthracycline-based chemotherapy (Anth-bC) are
attributed to cardiomyocyte injury due to DNA damage and altered mitochondrial bioenergetics leading to excess
reactive oxygen species and cell death. As a result, most research and treatment strategies are directed towards
preventing cardiomyocyte injury. Recently, evidence from our group demonstrates that cardiac fibrosis also
contributes to left ventricular dysfunction and heart failure symptoms following Anth-bC and now we have
evidence that doxorubicin (Dox, a widely used Anth-bC) has a direct effect on cardiac fibroblasts to produce
excess collagen. This project focuses on a candidate underlying mechanism by which Dox promotes cardiac
fibroblasts activation and fibrosis: a stress response known as cellular senescence. Cellular senescence is
characterized by permanent arrest of cell proliferation, mitochondrial dysfunction and development of a
senescence-associated secretory phenotype (SASP) producing inflammatory cytokines, chemokines and
proteases with both autocrine and paracrine effects. Although senescence has been studied in multiple cell
types, there are virtually no data on senescence in adult cardiac fibroblasts. We have now evidence that cardiac
fibroblasts exposed to Dox indeed develop mitochondrial dysfunction and become prematurely senescent.
However, even in well studied cell types a complete understanding of the SASP secretome and the exact nature
of the relationship between mitochondrial dysfunction and the senescence phenotype remain unclear. We
propose to use isolated adult rat cardiac fibroblasts and a clinically relevant rat model of cardiotoxicity to critically
determine the role of the secretome constituents in the activation of cardiac fibroblasts and the role mitochondrial
dysfunction in the development of senescence and its association to cardiac fibrosis and left ventricular
dysfunction. Our specific aims are designed to answer the following questions: 1) What are the proteomic
constituents of the cardiac fibroblast secretome induced by Dox that stimulate a pro-fibrotic phenotype; 2) is
there a causal role for mitochondria dysfunction in the development of Dox-induced senescence and SASP?;
and 3) to what extent cardiac fibroblasts senescence, SASP and mitochondrial dysfunction are associated with
the establishment and progression of myocardial fibrosis and LV dysfunction in vivo.
Through the accomplishment of these significant aims, this project will train the PI in new areas of mass
spectrometry-based proteomics, mitochondrial function and senescence biology. This training includes
workshops in proteomics, experiential learning and development of leadership skills. Ultimately, this will lead to
the success of her long term goal of becoming an independent funded investigator significantly contributing to
the understanding of the molecular and cellular causes of the cardiovascular toxicities of che...

## Key facts

- **NIH application ID:** 10363705
- **Project number:** 5K01HL145329-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Giselle C Melendez
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $118,382
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363705

## Citation

> US National Institutes of Health, RePORTER application 10363705, Cellular Senescence: A Novel Mechanism of Doxorubicin-Induced Cardiotoxicity (5K01HL145329-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10363705. Licensed CC0.

---

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