Pervasive environmental contaminant acrolein compromises myocardial geometry and function through the induction of cuproptosis.

Acrolein, a highly reactive α,β-unsaturated aldehyde found in cigarette smoke, automobile exhaust, industrial emissions, combustion byproducts, cooking and cyclophosphamide chemotherapy, has raised serious health concerns, although the precise mechanism remains unclear. This study is designed to examine the impact of this pervasive environmental pollutant on myocardial geometry and function alongside the underlying cellular mechanisms. Adult C57BL/6 mice are challenged with acrolein (2.5 mg/kg/day, i.p., for 20 days) prior to the evaluation of myocardial geometry and function. Acrolein exposure evokes evident cardiac remodeling (interstitial fibrosis), compromised echocardiographic (enlarged LVESD, compromised ejection fraction and fractional shortening), cardiomyocyte contractile and intracellular Ca 2+ capacities [decreased peak shortening, maximal velocity of shortening and relengthening (±dL/dt), and electrically stimulated rise in Fura-2 fluorescence intensity (ΔFFI), prolonged time-to-90% relengthening (TR 90) and intracellular Ca 2+ decay], accompanied by overt mitochondrial damage (ultrastructure, aconitase and mitochondrial protein contents), free radical buildup, apoptosis (Bax, Caspase-3, and Bcl2) and cuproptosis (upregulated SLC31A1, DLAT and FDX1), downregulated the Fe-S cluster proteins ACO2 and NDUFS8 alongside unchanged ATP7A and the ferroptosis markers GPX4 and SLC7A11. The levels of copper-sensing protein metal response element binding transcription factor 2 (MTF2), but not MTF1, are increased by acrolein insult. CB-DOCK2 analysis predicts an interaction between acrolein and the MTF2 dimer within its DNA-binding regions. In vivo administration of the cuproptosis inhibitor tetrathiomolybdate (TTM), the mitochondrial antioxidant mitoTEMPO or the nonselective MTF2 inhibitor actinomycin D alleviates acrolein-evoked cardiomyocyte dysfunction (decreased PS, ±dL/dt, and prolonged TR 90). These findings indicate that acrolein evoked cardiac functional anomalies possibly through MTF2-related control of cuproptosis.