Blocking Store-Operated Ca²⁺ Entry to Protect HL-1 Cardiomyocytes from Epirubicin-Induced Cardiotoxicity

Area of Science:

• Cardiology
• Molecular Biology
• Pharmacology

Background:

• Epirubicin (EPI) chemotherapy causes cardiotoxicity, limiting its use.
• Altered intracellular calcium (Ca2+) homeostasis contributes to EPI cardiotoxicity.
• The role of store-operated Ca2+ entry (SOCE) in EPI cardiotoxicity is unknown.

Purpose of the Study:

• To investigate the role of SOCE in epirubicin-induced cardiotoxicity.
• To determine the biphasic effect of EPI on SOCE in cardiomyocytes.
• To evaluate the therapeutic potential of SOCE blockers against EPI cardiotoxicity.

Main Methods:

• Analysis of RNA-seq data from human iPSC-derived cardiomyocytes treated with EPI.
• Measurement of SOCE in HL-1 cells using Fura-2 Ca2+ dye after EPI treatment.
• Assessment of apoptosis, cell size, hypertrophy markers, and NFAT4 translocation.
• Treatment with BTP2, a SOCE blocker, to evaluate protective effects.

Main Results:

• EPI significantly reduced SOCE gene expression in human cardiomyocytes.
• EPI initially increased SOCE and reactive oxygen species (ROS) in HL-1 cells, followed by a reduction.
• EPI induced apoptosis, hypertrophy, and NFAT4 translocation in HL-1 cells.
• BTP2 treatment mitigated EPI-induced SOCE enhancement, apoptosis, and hypertrophy.

Conclusions:

• EPI affects SOCE in a biphasic manner: initial enhancement followed by compensatory reduction.
• Early blockade of SOCE may protect cardiomyocytes from EPI-induced cardiotoxicity and hypertrophy.
• Targeting SOCE presents a potential therapeutic strategy against EPI cardiotoxicity.