Proteomic Profiling Reveals Roles of Stress Response, Ca²⁺ Transient Dysregulation, and Novel Signaling Pathways in Alcohol-Induced Cardiotoxicity

Background: Alcohol use in pregnancy increases the risk of abnormal cardiac development, and excessive alcohol consumption in adults can induce cardiomyopathy, contractile dysfunction, and arrhythmias. Understanding molecular mechanisms underlying alcohol-induced cardiac toxicity could provide guidance in the development of therapeutic strategies.

Methods: We have performed proteomic and bioinformatic analysis to examine protein alterations globally and quantitatively in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) treated with ethanol (EtOH). Proteins in both cell lysates and extracellular culture media were systematically quantitated.

Results: Treatment with EtOH caused severe detrimental effects on hiPSC-CMs as indicated by significant cell death and deranged Ca²⁺ handling. Treatment of hiPSC-CMs with EtOH significantly affected proteins responsible for stress response (e.g., GPX1 and HSPs), ion channel-related proteins (e.g. ATP1A2), myofibril structure proteins (e.g., MYL2/3), and those involved in focal adhesion and extracellular matrix (e.g., ILK and PXN). Proteins involved in the TNF receptor-associated factor 2 signaling (e.g., CPNE1 and TNIK) were also affected by EtOH treatment.

Conclusions: The observed changes in protein expression highlight the involvement of oxidative stress and dysregulation of Ca²⁺ handling and contraction while also implicating potential novel targets in alcohol-induced cardiotoxicity. These findings facilitate further exploration of potential mechanisms, discovery of novel biomarkers, and development of targeted therapeutics against EtOH-induced cardiotoxicity.