Temporal dynamics of PM2.5 induced cell death: Emphasizing inflammation as key mediator in the late stages of prolonged myocardial toxicity

Multiple forms of cell death contribute significantly to cardiovascular pathologies, negatively impacting cardiac remodeling and leading to heart failure. While myocardial cell death has been associated with PM_2.5 induced cardiotoxicity, the temporal dynamics of various cell death forms, such as apoptosis, ferroptosis, necroptosis, and pyroptosis, in relation to inflammatory processes, remain underexplored. This study examines the time-dependent onset and progression of these cell death pathways in the myocardium and their correlation with inflammation in a Wistar rat model. Female rats were exposed to 250 μg/m³ of PM_2.5 for 3 h daily over periods of 1, 7, 14, and 21 days. Gene expression analysis revealed that apoptotic markers (caspases 3, 7, and 9) were upregulated after 7 days of exposure, with continued elevation through 21 days. Ferroptotic markers, such as Ferritin and GPX4, declined significantly starting from day 14, while necroptosis (RIPK1) and pyroptosis (GSDMD) were prominent only after 21 days of exposure. In parallel, inflammatory markers, including IL-1β and TNF-α, showed substantial upregulation, particularly in the later stages, suggesting that inflammation plays a key role in amplifying myocardial damage in the prolonged exposure phase. These processes coincided with a progressive decrease in mitochondrial mass, elevated oxidative stress, and compromised bioenergetic function, all contributing to worsened cardiac function and remodeling by day 21.In conclusion, PM_2.5 exposure initiates myocardial damage primarily through apoptosis and ferroptosis in the early stages. However, prolonged exposure exacerbates cell death via necroptosis and pyroptosis, with inflammation emerging as a critical factor driving late-stage myocardial toxicity. This study highlights the temporal dynamics of distinct cell death pathways, offering crucial insights into the mechanisms of PM_2.5 induced cardiotoxicity and identifying potential therapeutic targets to mitigate its impact.