AHA Research – Circulation Research: Abstract 112: Doxorubicin Alters Cardiac Fibroblast Phenotype

The oldest cohort of childhood cancer survivors is entering into their sixth decade. The milestone comes with the knowledge that this population is at 15 times greater risk of cardiovascular events than the general population. One factor in this is doxorubicin, a chemotherapeutic drug commonly used to treat pediatric cancers. Our study investigates the effect of doxorubicin on proliferating cells in the heart, specifically, cardiac fibroblasts.

Doxorubicin inhibits cardiac fibroblast growth and migration. Cardiac fibroblasts also undergo a shift in gene expression when exposed to doxorubicin. Inflammatory cytokines and their receptors are upregulated, along with extracellular matrix regulatory proteins. ECM structural proteins and adhesion molecules are downregulated compared to control cells. Of note, monocyte chemoattractant protein-1, and its receptor C-C motif chemokine receptor-4, are upregulated over 40-fold compared to control cells.

Doxorubicin has multiple mechanisms of actions that target proliferating and non-proliferating cells differently. Cardiac fibroblasts are proliferative cells with a major role in multiple processes of cardiac homeostasis. This study lays the foundation of the phenotypic changes cardiac fibroblasts undergo when exposed to doxorubicin. These changes may create a microenvironment that primes the heart for adverse cardiac remodeling.