Vaping/e-cigarette-induced pulmonary extracellular vesicles contribute to exacerbated cardiomyocyte impairment through the translocation of ERK5

The impact of e-cigarettes/vaping on cardiac function remains contradictory owing to insufficient direct evidence of interorgan communication. Extracellular vesicles (EVs) have protective or detrimental effects depending on pathological conditions, making it crucial to understand their role in lung-cardiac cell interactions mediated by vaping inhalation. Pulmonary EVs were characterized from animals that underwent 12 weeks of nicotine inhalation (vaping component) (EVs Nicotine ) or vehicle control (EVs Vehicle ). EVs Nicotine significantly increased in size and abundance compared with EVs Vehicle . The direct effect of EVs Nicotine and EVs Vehicle on cardiomyocytes was then assessed in vitro and in vivo. EVs Nicotine led to a decrease in cardiac function as manifested by reduced cardiac contractility and impaired relaxation. EVs Nicotine induced increased levels of cleaved caspase-1 and cleaved caspase-11 in cardiomyocytes, indicating the promotion of pyroptosis. Meanwhile, EVs Nicotine stimulated the secretion of fibrotic factors. Further analysis revealed that nicotine inhalation stimulated EVs Nicotine enriched with high levels of ERK5 (EVs Nicotine -ERK5). It was discovered that these EVs derived from pulmonary epithelial cells. Furthermore, inhibiting cardiac ERK5 blunted the EVs Nicotine -induced pyroptosis and fibrotic factor secretion. We further identified GATA4, a pro-pyroptosis transcription factor, as being activated through ERK5-dependent phosphorylation. Our research demonstrates that nicotine inhalation exacerbates cardiac injury through the activation of EVs derived from the lungs during e-cigarettes/vaping. Specifically, the EVs containing ERK5 play a crucial role in mediating the detrimental effects on cardiac function. This research provides new insights into the cardiac toxicity of vaping and highlights the role of EVs Nicotine -ERK5 in this process.