Genetic alterations in coronary cell lines exposed to sirolimus and paclitaxel

Angioplasties using drug-eluting stents remain the most common and effective intervention for coronary artery disease. However, in-stent restenosis (ISR) continues to be the leading cause of stent failure following percutaneous coronary intervention, accounting for 5-10% of all clinical intervention procedures. This study aimed to investigate the potential molecular mechanisms involved in the development of in-stent restenosis. The cytotoxicity, genotoxicity, and transcriptional changes induced by sirolimus, paclitaxel, and mechanical stress were assessed in human coronary artery endothelial and smooth muscle cell lines. Both drugs were similarly effective in suppressing cell growth in these cell lines at different stages of the cell cycle. However, while paclitaxel primarily induced apoptosis, sirolimus caused cell death mainly through necrosis. Additionally, both drugs exhibited genotoxic effects, primarily increasing the levels of oxidized DNA nucleotide bases. Transcriptome analysis identified 23 differentially expressed genes with known biological functions in the chemically treated groups. Interestingly, transcriptomic alterations were also observed in coronary cells subjected solely to mechanical stress. In conclusion, our data confirm that sirolimus and paclitaxel inhibit cell proliferation through distinct mechanisms. Nonetheless, their genotoxic potential appears to act as a stimulus for cell proliferation, thereby increasing the risk of restenosis.