| objective :The migration and proliferation of vascular smooth muscle cells(VSMCs)are important mechanisms leading to restenosis after percutaneous transluminal coronary angioplasty(PCI).And drug-coated balloon(DCB)can prevent the formation of restenosis effectively by inhibiting intimal hyperplasia,which has been widely used in the field of vascular intervention.As mentioned above,the main mechanism of restenosis is the migration and proliferation of vascular smooth muscle cells(VSMC).Therefore,inhibition of intimal hyperplasia is an important approachs to prevent restenosis.It is important to explore the related mechanisms,and to develop new drug stents or other treatment methods in the treatment of restenosis.Gefitinib,as the third generation of anticancer drugs,is a selective epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs).Gefitinib could inhibit the proliferation of vascular smooth muscle cells more selectively.So,as a new DCB,gefitinib drug coated balloon plays an important role in the inhibition of intimal hyperplasia.In this study,the objective was to investigate whether gefitinib-coated balloons could inhibit cell proliferation,or facilitate cell apoptosis through suppressing the activity of PI3K/AKT signal pathway and affect the intimal hyperplasia,thus hindering the onset of restenosis after PCI.Methods :A total of 50 adult SD rats were randomly divided into 5 groups: sham group,model group,low-concentration gefitinib-coated balloon group,high-concentration gefitinib-coated balloon group and paclitaxel-coated balloon group.Rats in the sham group only received simple separation of right common carotid artery;while for rats in the model group,after separation of right common carotid artery,injuries were made using the ordinary balloon which deal with DMSO;balloons coated by gefitinib in different concentration and paclitaxel were used to make injuries in rats in other groups.4 weeks later,right common carotid arteries were collected from rats in each group for HE staining to observe the intimal proliferation of carotid artery;PCNA protein expression was detected via immunohistochemistry to investigate the cell proliferation;protein expressions of P-AKT and PI3 K were also assayed.Tunel staining was applied to detect the cell apoptosis.Results :1.Carotid artery stenosis can be improved by gefitinib and paclitaxel balloon.HE staining showed that: compared with the sham group,significant increase in the thickness of common carotid artery,and obvious stenosis in lumen were identified in the rats of model group(P<0.05).In comparison with the model group,alleviations were found in the hyperplasia of intima in common carotid arteries of the rats in the low-and high-concentration gefitinib-coated balloon groups and the paclitaxel-coated balloon group,and stenosis in lumen was also significantly improved(P<0.05).Compared with the paclitaxel-coated balloon group,The high concentration of gefitinib group are also significantly improved.2.Gefitinib can inhibit intimal hyperplasia.As showed in immunohistochemistry,compared with the sham group,the protein expressions of PCNA in the hyperplastic intima in common carotid arteries of rats in the model group were significantly augmented(P<0.01);in comparison with the model group,dramatic decreases were found in the protein expressions of PCNA in the hyperplastic intima in common carotid arteries of the rats in the gefitinib-coated balloon groups and the paclitaxel-coated balloon group,and stenosis in lumen was also significantly improved(P<0.05).3.Gefitinib doesn't increase the apoptosis of the intima.As is showed in Tunel staining,compared with the sham group,significant increase in the apoptotic cells in hyperplastic intima of common carotid artery in the rats of model group(P<0.01);in comparison with the model group,dramatic decreases were found in the apoptotic cells of the rats in the low-and high-concentration gefitinib-coated balloon groups and the paclitaxel-coated balloon group,and stenosis in lumen was also significantly improved(P<0.01).There was no significant increase in apoptosis.4.The expression of P13 K and P-AKT in intima can be reduced by gefitinib-coated balloon.As showed in immunohistochemistry,compared with the sham group,the protein expressions of P13 K and P-AKT in the hyperplastic intima in common carotid arteries of rats in the model group were significantly augmented(P<0.01);in comparison with the model group,dramatic decreases were found in the protein expressions of P13 K and P-AKT in the hyperplastic intima in common carotid arteries of the rats in the gefitinib-coated balloon groups and the paclitaxel-coated balloon group,and stenosis in lumen was also significantly improved(P<0.01).Compared with the high-concentration gefitinib-coated balloon groups,the protein expressions of P13 K in the hyperplastic intima in the paclitaxel-coated balloon group(P<0.05);Compared with the low-and high-concentration gefitinib-coated balloon groups,the protein expressions of P-AKT in the hyperplastic intima in the paclitaxel-coated balloon group(P<0.05);Conclusion :Gefitinib-coated balloon can suppress the excessive proliferation in the common carotid arterial intima of rats,which is superior to the paclitaxel-coated balloon;relevant mechanism for inhibiting the intimal hyperplasia might be correlated with the downregulated protein expression of PI3K/AKT signal pathway and inhibition on cell proliferation. |
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