ABC | Volume 112, Nº1, January 2019

Original Article Arq Bras Cardiol. 2019; 112(1):3-10 Tianshu-Chu et al Rapamycin combined with α -cyanoacrylate factors: NO, PGI2, cAMP and cGMP. They can also decrease intimal cholesterol and inhibit pro-atherosclerotic factors. 16 Outcomes in our experiment revealed that veins in the α -CA group had few fresh tissues and were easy to separate and had clear boundary from the surrounding tissues 4 weeks after the operation. The glue was not fully degraded and the intima of α -CA group was thinner than in the control group. Additionally, the percentage of PCNA-positive cells was significantly less than in the control group. Most importantly, α -CA as the extravascular supporter was able to inhibit intimal hyperplasia and enhance the patency rate. The proliferation, immigration, and secretion of vascular smooth muscle cells are key to intimal hyperplasia, which contribute to restenosis of vein grafts. Although certain drugs are effective for inhibiting intimal hyperplasia by inhibiting cytokinin and regulating cell cycle, severe toxic reactions and side effects limit their extensive use, as a consequence of which local application becomes particularly significant. RPM, colchicine, and other drugs are used locally on grafted veins. After anastomosis, these drugs are smeared evenly on grafted veins. RPM can accelerate vascular smooth muscle cells’ apoptosis by inhibiting the transformation of cells from G1 to S phase, thus suppressing vascular smooth muscle cells’ proliferation and immigration. Additionally, RPM protects endothelial cell function and reduces the release of vasoactive peptide when endothelial cells get injured. 17-19 Furthermore, RPM can also inhibit the differentiation, proliferation, and immigration of endothelial progenitor cells (EPC) and reduce NOS-mRNA expression in EPC. 20,21 Our results verified that veins in the RPM group had clear boundaries from the surrounding tissue; they were also fresh and clearly not expanded. Moreover, the intima of the RPM group was thinner than the control group’s and the percentage of PCNA‑positivecellswasremarkablylowerthaninthecontrolgroup. In summary, RPM may inhibit intimal hyperplasia and enhance patency rate. This study aimed to experiment the combination of an extravascular supporter and a local drug application. We chose α -CA as the extravascular supporter, RPM as the local application, and α -CA-RPM as the combination. α -CA-RPM was used in rat models of autogenous vein graft to stimulate grafted veins’ pathophysiological process after CABG. Interestingly, we found the percentage of PCNA-positive cells in the α -CA-RPM group was markedly less than in the control, α -CA, and RPM groups, which indicated that α -CA-RPM was more effective in inhibiting intimal hyperplasia than either α -CA or RPM separately. We concluded that α -CA-RPM can combine the effectiveness of extravascular supporters and local drugs and thus better inhibit intimal hyperplasia. Meanwhile, α -CA is an ideal carrier for the formulation of long-term control drug release which surrounds the vein graft tightly so that RPM will be released slowly and no RPM will be wasted. The endothelin-1 (ET-1) has been implicated in the pathogenesis of restenosis and vascular hypertrophy via enhancing aggregation of platelets and neutrophils, release of cytokine and chemokine, accumulation of endothelial cells, and promotiong of vascular smooth muscle cell migration towards the intimal layer. 22 Our results indicate that α -CA, RPM, and α -CA-RPM can stabilize endothelial cell function and diminish the release of ET-1 to inhibit intimal hyperplasia. An endothelin A/B receptor antagonist contributed to reduction of intimal hyperplasia in an organ culture of human saphenous veins and prevented neointimal development of coronary angioplasty in pigs, which is in accordance with our experiment. 23,24 α SMA is the specific protein of vascular smoothmuscle cells and the expression of α SMA can reflect the hyperplasia of vascular smooth muscle cells. In our experiment, we examined the values of α SMA in grafted veins with RT-PCR and found that the values in the α -CA, RPM, and α -CA-RPM groups was lower than in the control group. Notably, the value of the α ‑CA‑RPM group was lower than that of the α -CA and RPM groups. A study in which the α SMA component of vascular progenitor cells correlated with the coronary artery Gensini score also made the same point. 25 An experiment in a swine model of arteriovenous bypass grafting also provided tangible evidence to support this point of view. 26 The vWF is a glycoprotein encoded by the short arm of chromosome 12 and can be combined with collagen fibers and platelets; it is closely related to a range of cardiovascular diseases such as atherosclerosis, acute coronary syndrome, and atrial fibrillation. 27 vWF directly stimulates vascular smooth muscle cell proliferation, resulting in a direct dose‑response effect. It also accelerates intimal hyperplasia in intact endothelium without platelet activation or platelet-derived growth factor release. 28 Likewise, we found the vWF values of the α -CA, RPM, and α -CA-RPM groups was lower than that of the control group, and the α -CA-RPM group was lower than the α -CA or RPM groups. Our results in rats have been supported by experiments in other animals, such as an efficacy study in dogs and intimal hyperplasia of rabbit carotid arteries. 29,30 These results demonstrate that α -CA, RPM, and α -CA-RPMmight reduce intimal hyperplasia by blocking ET-1, α SMA, and vWF overexpression. Our results show that rapamycin combined with α -cyanoacrylate contributes to inhibiting intimal hyperplasia and is more effective for vascular patency than individual use of either α -CA or RPM in rat models 4 weeks after operation. The long-term effects of α -CA-RPM on vein graft remodeling are still unclear. Our team will conduct further research on intimal hyperplasia pathophysiological processes in pigs after CABG and the impacts of related interventions on grafted veins. Conclusion Our results confirmed that α -CA-RPM contributes to inhibiting intimal hyperplasia and is more effective for vascular patency than individual use either α -CA or RPM in rat models of artery bypass grafting. The positive effects appear to be associated with decreased intimal thickening, reduced cell proliferation in the vein graft, and decreased inflammatory responses. Although the shor-term effects of α -CA-RPM seem promising, the long-term effects and clinical significance of α -CA-RPM in CABG need to be studied in the future. Acknowledgements The authors would like to thank XR Huang and DK Huang for their expert technique. 8