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

Abstract

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 Ca2+ 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 (TR90) and intracellular Ca2+ 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 TR90). These findings indicate that acrolein evoked cardiac functional anomalies possibly through MTF2-related control of cuproptosis.

1. Introduction

Acrolein is a highly reactive α,β-unsaturated aldehyde and a pervasive environmental contaminant generated through the combustion of organic materials, including fossil fuels, tobacco, and high-temperature cooking of dietary fats, proteins, and carbohydrates [1–3]. It is also endogenously produced during lipid peroxidation and myeloperoxidase-mediated inflammatory responses and can arise as a toxic metabolite of chemotherapeutic agents such as cyclophosphamide [4–6]. Among its environmental sources, cigarette smoke represents a significant contributor to human acrolein exposure [3]. Cigarette smoking remains a major global health concern because of its strong association with a wide range of pathological conditions, including chronic obstructive pulmonary disease, cardiovascular and metabolic disorders, infertility, and cancer [7–9].

A growing body of research has highlighted the role of specific toxicants within cigarette smoke, such as acrolein, in driving genotoxic and mutagenic outcomes, thereby contributing to disease progression and premature mortality [9–14]. Owing to its potent electrophilic nature, acrolein readily forms covalent adducts with nucleophilic residues in proteins, lipids, and DNA, leading to oxidative stress, inflammation, and cellular dysfunction [5,15,16]. These molecular events underlie its involvement in diverse disease processes, including cardiovascular and neurodegenerative disorders, respiratory illness, and cancer [3,17]. Mechanistically, acrolein induces oxidative stress and mitochondrial dysfunction, yet the precise pathways linking acrolein exposure to cardiac pathology remain incompletely understood.