Study of preventing venous graft restenosis by local application of simvastatin and mechanical preconditioning_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHAO Chenyu ¹ , PAN Yuwei ² , JIA Liujun ³ , ZHANG Yan ¹ , DUAN Yabing ¹ , DING Li ¹ ,  SUN Hansong ¹

1. Department of Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100039, P. R. China;
2. Department of Biochemistry and Molecular Biology, College of Biology, China Agricultural University, Beijing, 100094, P. R. China;
3. Animal Laboratory Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 102300,P. R. China;

Corresponding author：

SUN Hansong, Email: drsunhs@sina.com

Keywords：

Local application; simvastatin; mechanical preconditioning; vein graft restenosis; coronary artery bypass grafting

DOI：

10.7507/1007-4848.202103021

Video：

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Objective To investigate the effect of simvastatin and mechanical pretreatment on intimal hyperplasia of venous graft and its mechanism.Methods Twelve New Zealand rabbits were selected and randomly divided into 4 groups: a blank control group, a simvastatin topical treatment group, a mechanical precondition group and a combined group (n=3 in each group). Ultrasound was used to evaluate the changes of graft wall and blood flow velocity in the graft, and pathological section was used to evaluate the intimal hyperplasia. Human umbilical cord endodermal cells were cultured in vitro. A simvastatin group and a solvent control group were set to detect YAP phosphorylation, downstream target gene expression and cell proliferation.Results Vascular ultrasound showed that except the simvastatin topical treatment group, the flow velocity in vein grafts in the other three groups significantly increased 21 days after surgery compared with 7 days after surgery (P<0.01). Pathological sections showed that the thickness of new intima in the simvastatin topical treatment group, mechanical precondition group, combined group and blank control group were 45.56±4.11 μm, 201.28±16.71 μm, 143.57±7.82 μm, 249.45±13.33 μm, respectively, and there were statistical differences compared with the blank control group (P<0.05). In vitro results showed that compared with the solvent control group, cell death was observed in high concentration simvastatin (5 mmol/L) group, cell proliferation was inhibited in low concentration simvastatin (2.5 mmol/L) group (P<0.05), the expression of YAP protein in the simvastatin group was unchanged, but the expression of phosphorylated YAP protein significantly increased (P<0.05), and the expression of downstream target gene ccn1 was down-regulated (P<0.001).Conclusion Intravascular local application of simvastatin and mechanical preconditioning alone or in combination can inhibit intimal hyperplasia of venous graft. High concentration of simvastatin has cytotoxicity, while low concentration of simvastatin has inhibitory effect on cell proliferation. Simvastatin can inhibit the formation of new intima by inhibiting the entry of YAP into the nucleus and reducing the transcription of cell proliferation-related target gene ccn1.

Citation： ZHAO Chenyu, PAN Yuwei, JIA Liujun, ZHANG Yan, DUAN Yabing, DING Li, SUN Hansong. Study of preventing venous graft restenosis by local application of simvastatin and mechanical preconditioning. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(2): 291-298. doi: 10.7507/1007-4848.202103021 Copy

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6.	Zhang L, Freedman NJ, Brian L, et al. Graft-extrinsic cells predominate in vein graft arterialization. Arterioscler Thromb Vasc Biol, 2004, 24(3): 470-476.
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8.	Node K, Fujita M, Kitakaze M, et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003, 108(7): 839-843.
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10.	Oesterle A, Liao JK. The pleiotropic effects of statins—From coronary artery disease and stroke to atrial fibrillation and ventricular tachyarrhythmia. Curr Vasc Pharmacol, 2019, 17(3): 222-232.
11.	Do e Z, Fukumoto Y, Sugimura K, et al. Rho-kinase activation in patients with heart failure. Circ J, 2013, 77(10): 2542-2550.
12.	Kang S, Kim K, Noh JY, et al. Simvastatin induces the apoptosis of normal vascular smooth muscle through the disruption of actin integrity via the impairment of RhoA/Rac-1 activity. Thromb Haemost, 2016, 116(3): 496-505.
13.	Hwang AR, Han JH, Lim JH, et al. Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells. PLoS One, 2017, 12(5): e0178278.
14.	Abdullah S, Jarrar Y, Alhawari H, et al. The influence of endothelial nitric oxide synthase (eNOS) genetic polymorphisms on cholesterol blood levels among type 2 diabetic patients on atorvastatin therapy. Endocr Metab Immune Disord Drug Targets, 2021, 21(2): 352-359.
15.	Sanvee GM, Panajatovic MV, Bouitbir J, et al. Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle. Biochem Pharmacol, 2019, 164: 23-33.
16.	Wang L, Luo JY, Li B, et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature, 2016, 540(7634): 579-582.
17.	Buttitta LA, Edgar BA. How size is controlled: From Hippos to Yorkies. Nat Cell Biol, 2007, 9(11): 1225-1227.
18.	Pan D. Hippo signaling in organ size control. Genes Dev, 2007, 21(8): 886-897.
19.	He J, Bao Q, Yan M, et al. The role of Hippo/YES-associated protein signalling in vascular remodelling associated with cardiovascular disease. Br J Pharmacol, 2018, 175(8): 1354-1361.
20.	Grzeszkiewicz TM, Lindner V, Chen N, et al. The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. Endocrinology, 2002, 143(4): 1441-1450.
21.	Ruiter MS, Pesce M. Mechanotransduction in coronary vein graft disease. Front Cardiovasc Med, 2018, 5: 20.
22.	Kimura TE, Duggirala A, Smith MC, et al. The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP. J Mol Cell Cardiol, 2016, 90: 1-10.

1. Spadaccio C, Benedetto U. Coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) in the treatment of multivessel coronary disease: Quo vadis?—A review of the evidences on coronary artery disease. Ann Cardiothorac Surg, 2018, 7(4): 506-515.
2. 乐士冠, 肖健, 奚望, 等. 冠状动脉旁路移植术后静脉桥血管再狭窄的机制研究进展. 第二军医大学学报, 2017, 38(5): 639-645.
3. Caliskan E, de Souza DR, Böning A, et al. Saphenous vein grafts in contemporary coronary artery bypass graft surgery. Nat Rev Cardiol, 2020, 17(3): 155-169.
4. Obed D, Fleissner F, Martens A, et al. Total arterial revascularization with radial artery and internal thoracic artery T-grafts is associated with superior long-term survival in patients undergoing coronary artery bypass grafting. Ann Thorac Cardiovasc Surg, 2020, 26(1): 30-39.
5. Guida G, Ward AO, Bruno VD, et al. Saphenous vein graft disease, pathophysiology, prevention, and treatment. A review of the literature. J Card Surg, 2020, 35(6): 1314-1321.
6. Zhang L, Freedman NJ, Brian L, et al. Graft-extrinsic cells predominate in vein graft arterialization. Arterioscler Thromb Vasc Biol, 2004, 24(3): 470-476.
7. Dianati Maleki N, Ehteshami Afshar A, Parikh PB. Management of saphenous vein graft disease in patients with prior coronary artery bypass surgery. Curr Treat Options Cardiovasc Med, 2019, 21(2): 12.
8. Node K, Fujita M, Kitakaze M, et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003, 108(7): 839-843.
9. Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol, 2004, 43(4): 642-648.
10. Oesterle A, Liao JK. The pleiotropic effects of statins—From coronary artery disease and stroke to atrial fibrillation and ventricular tachyarrhythmia. Curr Vasc Pharmacol, 2019, 17(3): 222-232.
11. Do e Z, Fukumoto Y, Sugimura K, et al. Rho-kinase activation in patients with heart failure. Circ J, 2013, 77(10): 2542-2550.
12. Kang S, Kim K, Noh JY, et al. Simvastatin induces the apoptosis of normal vascular smooth muscle through the disruption of actin integrity via the impairment of RhoA/Rac-1 activity. Thromb Haemost, 2016, 116(3): 496-505.
13. Hwang AR, Han JH, Lim JH, et al. Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells. PLoS One, 2017, 12(5): e0178278.
14. Abdullah S, Jarrar Y, Alhawari H, et al. The influence of endothelial nitric oxide synthase (eNOS) genetic polymorphisms on cholesterol blood levels among type 2 diabetic patients on atorvastatin therapy. Endocr Metab Immune Disord Drug Targets, 2021, 21(2): 352-359.
15. Sanvee GM, Panajatovic MV, Bouitbir J, et al. Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle. Biochem Pharmacol, 2019, 164: 23-33.
16. Wang L, Luo JY, Li B, et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature, 2016, 540(7634): 579-582.
17. Buttitta LA, Edgar BA. How size is controlled: From Hippos to Yorkies. Nat Cell Biol, 2007, 9(11): 1225-1227.
18. Pan D. Hippo signaling in organ size control. Genes Dev, 2007, 21(8): 886-897.
19. He J, Bao Q, Yan M, et al. The role of Hippo/YES-associated protein signalling in vascular remodelling associated with cardiovascular disease. Br J Pharmacol, 2018, 175(8): 1354-1361.
20. Grzeszkiewicz TM, Lindner V, Chen N, et al. The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. Endocrinology, 2002, 143(4): 1441-1450.
21. Ruiter MS, Pesce M. Mechanotransduction in coronary vein graft disease. Front Cardiovasc Med, 2018, 5: 20.
22. Kimura TE, Duggirala A, Smith MC, et al. The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP. J Mol Cell Cardiol, 2016, 90: 1-10.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Study of preventing venous graft restenosis by local application of simvastatin and mechanical preconditioning

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