Investigating the ability of statin-mediated ERK5 activation to protect cardiac microvascular endothelial cells and cardiomyocytes against the adverse effects of doxorubicin.

Abstract

Doxorubicin is a widely used chemotherapeutic agent known for its efficacy against various cancers; however, its clinical utility is limited by cardiotoxic side effects that involve both endothelial dysfunction and direct cardiomyocyte damage. This doctoral research investigates the protective role of statins—specifically simvastatin and atorvastatin—in mitigating doxorubicin-induced toxicity through activation of the ERK5 signaling pathway. Using human and mouse cardiac microvascular endothelial cells (HCMECs and MCMECs), as well as human cardiomyocyte-like AC16 cells, the study demonstrates that statins restore ERK5 phosphorylation and upregulate vasoprotective transcription factors KLF2 and KLF4. These molecular changes were associated with decreased inflammatory marker expression, preserved tight junction integrity, and improved cellular viability. The findings highlight a novel therapeutic potential for statins in preserving cardiovascular health during chemotherapy and underscore the significance of ERK5 as a molecular target for cardioprotection.