Doxorubicin Induces Endothelial Dysfunction via Immune Activation

Doxorubicin, often called the “Red Devil” for its potent side effects, induces cardiotoxicity by impairing endothelial function and promoting vascular dysfunction. We aim to investigate how this cardiotoxicity is linked to immune activation, potentially mediated by HERV-K release triggered by doxorubicin.

In vitro + ex-vivo research + in-silico analysis

Cancer drugs are designed to kill tumor cells, but sometimes they can also harm healthy parts of the body. One such drug, doxorubicin, is very effective in treating cancer, but it can cause serious side effects in the heart and blood vessels. While scientists already understand how it damages heart muscle cells, we are now discovering that the immune system and blood vessel lining (endothelium) may also play an important role in this damage.

In this project, we are studying how a type of immune cell called a monocyte responds to doxorubicin. When exposed to this drug, these cells may activate certain hidden genetic elements in our DNA called HERV-K (human endogenous retrovirus-K). These are ancient viral sequences normally kept “silent” in our genome, but under stress or inflammation, they can become active and trigger harmful effects.

Our early findings suggest that doxorubicin changes a protein called KAP1 (TRIM28) through a process called phosphorylation. This change may “unlock” HERV-K, allowing it to become active. Once activated, monocytes may release inflammatory signals and tiny particles called exosomes, which can travel through the blood and damage the cells lining blood vessels.

This damage can weaken the barrier function of blood vessels, leading to vascular leakage, inflammation, and potentially serious heart problems, including sudden cardiac events. Interestingly, similar mechanisms have been observed in diseases like pulmonary hypertension, suggesting a shared pathway of injury.

To better understand this, our study will:

• Examine how doxorubicin induces harmful signals and exosomes released by monocytes

• Test how these signals affect blood vessel cells

• Explore if HERV-K levels in blood can serve as a biomarker for cardiac side effects in cancer patients on doxorubicin.