ABC | Volume 112, Nº1, January 2019

Original Article Rapamycin Combined with α-Cyanoacrylate Contributes to Inhibiting Intimal Hyperplasia in Rat Models Tianshu-Chu, Congrong-Gao, Zhiwei-zhao, Fei-Ling, Ayu-Sun, Yuanbiao-Zheng, Jing-Cao, Jianjun Ge Anhui Medical University, Hefei – China Mailing Address: Jianjun Ge • 17 # Lujiang Road, Hefei 230001, P.R. – China E-mail: SLGejianjun@outlook.com Manuscript received November 06, 2017, revised manuscript June 26, 2018, accepted July 23, 2018 DOI: 10.5935/abc.20180247 Abstract Background: Vein graft restenosis has an adverse impact on bridge vessel circulation and patient prognosis after coronary artery bypass grafting. Objectives: We used the extravascular supporter α -cyanoacrylate ( α -CA), the local application rapamycin/sirolimus (RPM), and a combination of the two ( α -CA-RPM) in rat models of autogenous vein graft to stimulate vein graft change. The aim of our study was to observe the effect of α -CA, RPM, and α -CA-RPM on vein hyperplasia. Methods: Fifty healthy Sprague Dawley (SD) rats were randomized into the following 5 groups: sham, control, α -CA, RPM, and α -CA-RPM. Operating procedure as subsequently described was used to build models of grafted rat jugular vein on carotid artery on one side. The level of endothelin-1 (ET-1) was determined by enzyme-linked immunosorbent assay (ELISA). Grafted veins were observed via naked eye 4 weeks later; fresh veins were observed via microscope and image-processing software in hematoxylin-eosin (HE) staining and immunohistochemistry after having been fixed and stored” (i.e. First they were fixed and stored, and second they were observed); α -Smooth Muscle Actin ( α SMA) and von Willebrand factor (vWF) were measured with reverse transcription-polymerase chain reaction (RT-PCR). Comparisons were made with single‑factor analysis of variance and Fisher’s least significant difference test, with p < 0.05 considered significant. Results: We found that intimal thickness of the α -CA, RPM, and α -CA-RPM groups was lower than that of the control group (p < 0.01), and the thickness of the α -CA-RPM group was notably lower than that of the α -CA and RPM groups (p < 0.05). Conclusion: RPM combined with α -CA contributes to inhibiting intimal hyperplasia in rat models and is more effective for vascular patency than individual use of either α -CA or RPM. (Arq Bras Cardiol. 2019; 112(1):3-10) Keywords: Myocardial Revascularization/surgery; Cyanocrylates; Sirolimus; Hyperplasia; Graft Occlusion, Vascular; Vascular Patency; Rats. Introduction Coronary artery bypass grafting (CABG) is one of the main therapies for coronary heart disease. However, 40% of bridge vessels are totally obstructed and 30%of bridge vessel blood flow is reduced after CABG, which seriously affects patient survival and prognosis. 1,2 Mechanisms of restenosis include thrombosis, intimal hyperplasia, and atherosclerosis. Immigration of endothelial cells and vascular smooth muscle cells is vital for intimal hyperplasia, which is the main cause of restenosis. 3 Although drugs for inhibiting cytokinin and cell cycle regulation contribute to inhibiting intimal hyperplasia, the systemic side effects are harmful for patients. Therefore, local application is very important. Rapamycin (sirolimus) is widely used for anti-rejection after transplant operations, and drug‑eluting stents are widely used in coronary arteries. Researchers have found that applying rapamycin to grafted veins is effective in inhibiting intimal hyperplasia by inhibiting proliferation and promoting apoptosis of smooth muscle cells. 4 In 1963, Parsonnet et al. observed that perivenous supporters were effective for vascular patency. 5 Subsequently, basic and clinical researchers found that perivenous supporters could enhance patency rates by reducing intimal hyperplasia in grafted veins. α -CA, which is liquid at room temperature, is harmless to the human body. Degradation time is 1-3 months, depending on the dosage. α -CA is used in surgery for bleeding closure and wound binding. 6 α -CA and RPM are usually used as perivenous supporters and local applications, respectively. We innovatively investigated the pathophysiological process of neointima hyperplasia in grafted veins after CABG via rat models of autogenous vein graft. We are interested in finding new methods to inhibit intimal hyperplasia. Methods Reagent and method α -CA (99% n-octyl- α -cyanoacrylate + n-butyl- α - cyanoacrylate) was purchased from Beijing Fuaile Science and Technology Development Co. (Beijing, China). RPM was purchased from Selleck Company. We dissolved 8mg of RPM in 3