Proteomic profiling reveals dysregulated mitochondrial complex subunits responsible for myocardial toxicity induced by SiNPs

The relationship between environmental exposure to silica nanoparticles (SiNPs) and adverse cardiac outcomes has received more attention. Our recent work has revealed a size-dependent impact of the intratracheal instilled SiNPs on cardiac health of ApoE−/− mice using nanoscale SiNPs-60 and submicro-sized SiNPs-300, but the underlying mechanism of action still remains unclear. Hence, we identified proteins and protein networks perturbed by SiNPs in myocardial tissues of ApoE−/− mice by using LC-MS/MS-based quantitative proteomics. A set of 435 differentially expressed proteins (DEPs) were screened in response to SiNPs, which mainly enriched in the mitochondria and functioned in cell metabolism, biosynthesis and signal transduction. KEGG analysis showed that DEPs were significantly associated with oxidative phosphorylation and cardiomyopathy. The protein-protein interaction (PPI) network revealed 9 DEPs (e.g., Ndufs1, Ndufv1, Cox4i1) as potential biomarkers of SiNPs-induced myocardial toxicity. Of note, all the 9 candidate proteins were subunits of mitochondria respiratory chain complex, and their expressions were dependent on particle size, which were remarkably down-regulated by SiNPs-60 but not by SiNPs-300. More importantly, the correlation analysis verified the 9 dysregulated mitochondria complex protein subunits strongly correlated to the biochemical and functional indexes of cardiac injury in response to SiNPs. In conclusion, our study firstly provided significant proteomic insights into the potential molecular mechanisms underlying SiNPs-elicited cardiotoxicity, with the dysregulated mitochondrial complex subunits as core regulatory molecules. Overall, our study would provide the scientific basis for the molecular actions and mechanisms of toxicity induced by SiNPs.