SRM 1650b Administration to Isolated Rat Heart Aggravates Ischemia-Reperfusion Injury via Mitochondrial Dysfunction and Downregulation of PI3K/Akt Signaling Pathways.

Numerous studies have demonstrated an association between diesel particulate matter (DPM) exposure and cardiotoxicity; recent evidence further suggests that cardiomyocytes may directly internalize DPM. In the present study, we investigated the cardiotoxic effects of SRM 1650b, a representative heavy-duty diesel emission particulate standard, which is considered a major contributor to the ongoing air pollution crisis. Isolated male Wistar rat hearts were perfused with different concentrations of SRM 1650b following stabilization, followed by 30 min of ischemia and 60 min of reperfusion. Results demonstrated deteriorated cardiac hemodynamics and elevated tissue injury compared with normal controls across different concentrations of SRM 1650b (HC, highest concentration = 300 μg/mL; MC, medium concentration = 100 μg/mL; LC, low concentration = 10 μg/mL). Administration of SRM 1650b significantly increased oxidative stress in both cardiac tissue and mitochondria. It also induced a decline in mitochondrial bioenergetic enzyme activities and corresponding respiratory efficiency compared with normal controls. The expression of mitochondrial quality-control-associated genes, including Pgc-1α, Tfam, Polg, Fis1, Mfn1, and Pink1, was significantly reduced, along with a decline in mitochondrial DNA copy number. Collectively, these alterations resulted in heightened myocardial sensitivity to ischemia-reperfusion injury. Furthermore, expression of the PI3K/Akt signaling pathway was reduced following SRM 1650b administration and decreased further after ischemia-reperfusion challenge. These findings suggest that SRM 1650b-mediated cardiotoxicity is associated with impaired mitochondrial functional integrity and suppressed PI3K/Akt signaling, thereby reducing the cardiac capacity to withstand ischemia-reperfusion injury.