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Gap junction intercellular communication(GJIC)between cardiomyocytes is essential for synchronous heart contraction and relies on Connexin(Cx)-containing channels.Connexin(Cx)43 is a major component involved in GJIC in heart tissue and its abnormal expression is closely associated with various cardiac diseases.Silica nanoparticles are known to induce cardiovascular toxicity,however,the mechanisms whereby role of GJIC in cardiomyocytes cell apoptosis induced by silica nanoparticles remains unknown.The aim of the present study was to determine whether silica nanoparticles-induced inhibition of GJIC and reduced Cx43 expression promote rat cardiomyocytes cell line(H9c2 cells)loss using CCK-8 Kit,Scrape Load Dye Transfer Technique(SLDT),Annexin V/PI double staining assays and Western blot analysis.The results showed that silica nanoparticles-induced cytotoxicity was demonstrated in rat H9c2 cells with cell viability in a time-and concentration-dependent manner.And silica nanoparticles induced the decrease of GJIC activity in H9c2 cells with a concentration-dependent manner through downregulation of Cx43 and upregulation of P-Cx4.Inhibition of gap junctions by gap junction blocker carbenoxolone disodium(CBX)resulted in decreased survival/increased apoptosis while enhancement of gap junctions by retinoic acid(RA)led to enhanced survival/decreased apoptosis.Furthermore,silica nanoparticles inducing apoptosis exerted through the functional gap junction was correlated with the mitochondrial pathway-related apoptosis protein Bcl-2/Bax,CytC Caspase-9 and Caspase-3.Taken together,our results provide the first evidence that Silica nanoparticles–decreased gap junctional intercellular communication promotes apoptosis in H9c2 cardiomyocytes cells via the mitochondrial pathway.In addition,downregulation of GJIC induced by silica nanoparticles in H9c2 cells through downregulation of Cx43 and upregulation of P-Cx43.These results suggested that in rat cardiomyocytes cell line,GJIC plays a protective role in silica nanoparticles-induced apoptosis and GJIC may be one of the targets for silica nanoparticles biological effects.