Silica nanoparticles (SiNPs), as one of the most widely produced nanomaterials globally, have garnered widespread attention for their potential toxicity. Epidemiological and experimental evidence have illuminated that exposure to SiNPs can lead to cardiovascular toxicity, though the precise underlying mechanisms remain unclear. We previously identified PKA as a crucial regulator in SiNPs-elicited myocardial injury. Considering this, we further conducted validation in an animal model and also an in-depth investigation into the mechanisms involved. Our data manifested that the pharmacological activation of PKA via intraperitoneal administration of Forskolin greatly mitigated SiNPs-induced abnormalities in histology and function of the rat heart, along with lessening cardiac oxidative stress and mitochondrial damage. Concomitantly, copper overload was present in the rat heart and cardiomyocytes with SiNPs administration. Notably, PKA inhibition could worsen this phenomenon, whilst PKA activation alleviated it. The mechanistic investigation hinted at the PKA/DRP1/ATP7B signaling to modulate mitochondrial dysfunction and copper overload in cardiomyocytes and ultimately apoptosis caused by SiNPs. • Increased SiNPs exposure and ensuing health effect should be concerned. • PKA functions as a protective factor in SiNPs-elicited myocardial toxicity. • PKA modulates DRP1/ATP7B signaling to mitigate myocardial injury caused by SiNPs. • PKA activation improves myocardial mitochondrial health and copper homeostasis.
Guo et al. (Sun,) studied this question.