Mosaic adeno-associated virus-mediated gene transfer of calcitonin gene-related peptide for prevention of inflammatory mediator expression, macrophage infiltration and neointimal hyperplasia in an experimental rabbit vein graft model_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

 ZHANG Xiaoning ^1,2 , ZHUANG Jian ¹ , WU Hongsui ¹ , CHEN Zhihong ¹ , SU Jian ¹ , CHEN Shiliang ¹ , CHEN Jianguang ¹

1. Department of Cardiovascular Surgery, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, 510080, P.R.China;
2. Department of Cardiothoracic Surgery, Heze Traditional Chinese Medicine Hospital, Heze, 274000, Shandong, P.R.China;

Corresponding author：

ZHANG Xiaoning, Email: xiaoningzhang@msn.com

Keywords：

Vein graft disease; calcitonin gene-related peptide; gene therapy

DOI：

10.7507/1007-4848.201604054

Video：

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Objective To investigate the effect and mechanism of calcitonin gene-related peptide (CGRP) on the prevention and treatment of transplant vein graft disease. Methods The 25 New Zealand white rabbits were divided into three groups: an experimental group [n=8, the rabbit jugular veins transfected with adeno-associated virus vector tipe 2/1 containing CGRP gene (AAV2/1-CGRP)], a carrier group [n=9, transfected with mosaic adeno-associated virus vector tipe 2/1 containing LacZ gene (AAV2/1-LacZ)] and a control group (n=8, saline) and then the cervical veins were implantated into the ipsilateral carotid artery by reverse end-side anastomosis. At 4 weeks after surgery, the pathology of the specimens, CD68 immunohistochemistry, in situ β-galactosidase staining were obtained. The expression of CGRP gene was detected by reverse transcription-polymerase chain reaction (RT-PCR). Monocyte chemoattractant protein-1(MCP-1), tumour necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-9 (MMP-9) were detected by real-time polymerase chain reaction (real-time PCR). Results The CGRP and LacZ gene expression was positive at postoperative 4 weeks. The intima/media ratio was significantly inhibited in the experimental group. Macrophage infiltration and expression of inflammatory mediators including MCP-1, TNF-α, iNOS and MMP-9 were also significantly inhibited in the experimental group. Conclusion Transfection of AAV2/1-CGRP inhibits inflammatory mediator expression, macrophage infiltration and neointimal hyperplasia in experimental vein graft disease.

Citation： ZHANG Xiaoning, ZHUANG Jian, WU Hongsui, CHEN Zhihong, SU Jian, CHEN Shiliang, CHEN Jianguang. Mosaic adeno-associated virus-mediated gene transfer of calcitonin gene-related peptide for prevention of inflammatory mediator expression, macrophage infiltration and neointimal hyperplasia in an experimental rabbit vein graft model. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2017, 24(11): 880-885. doi: 10.7507/1007-4848.201604054 Copy

1.	曹剑, 屈正. 冠状动脉旁路移植术后移植静脉再狭窄的防治现状. 中国胸心血管外科临床杂志, 2010, 17(6): 499-502.
2.	Li W, Wang T, Ma C, et al. Calcitonin gene-related peptide inhibits interleukin-1beta-induced endogenous monocyte chemoattractant protein-1 secretion in type II alveolar epithelial cells. Am J Physiol Cell Physiol, 2006, 291(3): C456-C465.
3.	Huang J, Stohl LL, Zhou X, et al. Calcitonin gene-related peptide inhibits chemokine production by human dermal microvascular endothelial cells. Brain Behav Immun, 2011, 25(4): 787-799.
4.	Fang L, Chen MF, Xiao ZL, et al. Calcitonin gene-related peptide released from endothelial progenitor cells inhibits the proliferation of rat vascular smooth muscle cells induced by angiotensin Ⅱ. Mol Cell Biochem, 2011, 355(1-2): 99-108.
5.	Zucker KE, Kamberi P, Sobel RA, et al. Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis. Clin Exp Immunol, 2006, 143(3): 458-466.
6.	Kilian EG, Eifert S, Beiras-Fernandez A, et al. Adeno-associated virus-mediated gene transfer in a rabbit vein graft model. Circ J, 2008, 72(10): 1700-1704.
7.	Sen S, Conroy S, Hynes SO, et al. Gene delivery to the vasculature mediated by low-titre adeno-associated virus serotypes 1 and 5. Gene Med, 2008, 10(2): 143-151.
8.	Stachler MD, Bartlett JS. Mosaic vectors comprised of modified AAV1 capsid proteins for efficient vector purification and targeting to vascular endothelial cells. Gene Ther, 2006, 13(11): 926-931.
9.	Bidzhekov K, Zernecke A, Weber C. MCP-1 induces a novel transcription factor with proapoptotic activity. Circ Res, 2006, 98(9): 1107-1109.
10.	Stark VK, Hoch JR, Warner TF, et al. Monocyte chemotactic protein-1 expression is associated with the development of vein graft intimal hyperplasia. Arterioscler Thromb Vasc Biol, 1997, 17(8): 1614-1621.
11.	Fu C, Yu P, Tao M, et al. Monocyte chemoattractant protein-1/CCR2 axis promotes vein graft neointimal hyperplasia through its signaling in graft-extrinsic cell populations. Arterioscler Thromb Vasc Biol, 2012, 32(10): 2418-2426.
12.	Tatewaki H, Egashira K, Kimura S, et al. Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein graft neointimal formation. J Vasc Surg, 2007, 45(6): 1236-1243.
13.	Yang L, Sakurai T, Kamiyoshi A, et al. Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury. J Mol Cell Cardiol, 2013, 59: 55-66.
14.	Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 2005, 352(16): 1685-1695.
15.	Wong AP, Nili N, Jackson ZS, et al. Expansive remodeling in venous bypass grafts: Novel implications for vein graft disease. Atherosclerosis, 2008, 196(2): 580-589.
16.	Berard X, Déglise S, Alonso F, et al. Role of hemodynamic forces in the ex vivo arterialization of human saphenousveins. J Vasc Surg, 2013, 57(5): 1371-1382.
17.	Ma L, Guan YQ, Du ZD. Salvianolic Acid B Down-regulates Matrix Metalloproteinase-9 Activity and Expression in Tumor Necrosis Factor-α-induced Human Coronary Artery Endothelial Cells. Chin Med J(Engl), 2015, 128(19): 2658-2663.
18.	Yu YM, Lin HC, Chang WC. Carnosic acid prevents the migration of human aortic smooth muscle cells by inhibiting the activation and expression of matrix metalloproteinase-9. Br J Nutr, 2008, 100(4): 731-738.
19.	Lee SO, Jeong YJ, Yu MH, et al. Wogonin suppresses TNF-alpha-induced MMP-9 expression by blocking the NF-kappaB activation via MAPK signaling pathways in human aortic smooth muscle cells. Biochem Biophys Res Commun, 2006, 351(1): 118-125.
20.	Egi K, Conrad NE, Kwan J, et al. Inhibition of inducible nitric oxide synthase and superoxide production reduces matrix metalloproteinase-9 activity and restores coronary vasomotor function in rat cardiac allografts. Eur J Cardiothorac Surg, 2004, 26(2): 262-269.
21.	Hayashi T, Matsui-Hirai H, Fukatsu A, et al. Selective iNOS inhibitor, ONO1714 successfully retards the development of high-cholesterol diet induced atherosclerosis by novel mechanism. Atherosclerosis, 2006, 187(2): 316-324.
22.	Feng Y, Tang Y, Guo J, et al. Inhibition of LPS-induced TNF-alpha production by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. Life Sci, 1997, 61(20): PL281-PL287.

1. 曹剑, 屈正. 冠状动脉旁路移植术后移植静脉再狭窄的防治现状. 中国胸心血管外科临床杂志, 2010, 17(6): 499-502.
2. Li W, Wang T, Ma C, et al. Calcitonin gene-related peptide inhibits interleukin-1beta-induced endogenous monocyte chemoattractant protein-1 secretion in type II alveolar epithelial cells. Am J Physiol Cell Physiol, 2006, 291(3): C456-C465.
3. Huang J, Stohl LL, Zhou X, et al. Calcitonin gene-related peptide inhibits chemokine production by human dermal microvascular endothelial cells. Brain Behav Immun, 2011, 25(4): 787-799.
4. Fang L, Chen MF, Xiao ZL, et al. Calcitonin gene-related peptide released from endothelial progenitor cells inhibits the proliferation of rat vascular smooth muscle cells induced by angiotensin Ⅱ. Mol Cell Biochem, 2011, 355(1-2): 99-108.
5. Zucker KE, Kamberi P, Sobel RA, et al. Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis. Clin Exp Immunol, 2006, 143(3): 458-466.
6. Kilian EG, Eifert S, Beiras-Fernandez A, et al. Adeno-associated virus-mediated gene transfer in a rabbit vein graft model. Circ J, 2008, 72(10): 1700-1704.
7. Sen S, Conroy S, Hynes SO, et al. Gene delivery to the vasculature mediated by low-titre adeno-associated virus serotypes 1 and 5. Gene Med, 2008, 10(2): 143-151.
8. Stachler MD, Bartlett JS. Mosaic vectors comprised of modified AAV1 capsid proteins for efficient vector purification and targeting to vascular endothelial cells. Gene Ther, 2006, 13(11): 926-931.
9. Bidzhekov K, Zernecke A, Weber C. MCP-1 induces a novel transcription factor with proapoptotic activity. Circ Res, 2006, 98(9): 1107-1109.
10. Stark VK, Hoch JR, Warner TF, et al. Monocyte chemotactic protein-1 expression is associated with the development of vein graft intimal hyperplasia. Arterioscler Thromb Vasc Biol, 1997, 17(8): 1614-1621.
11. Fu C, Yu P, Tao M, et al. Monocyte chemoattractant protein-1/CCR2 axis promotes vein graft neointimal hyperplasia through its signaling in graft-extrinsic cell populations. Arterioscler Thromb Vasc Biol, 2012, 32(10): 2418-2426.
12. Tatewaki H, Egashira K, Kimura S, et al. Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein graft neointimal formation. J Vasc Surg, 2007, 45(6): 1236-1243.
13. Yang L, Sakurai T, Kamiyoshi A, et al. Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury. J Mol Cell Cardiol, 2013, 59: 55-66.
14. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 2005, 352(16): 1685-1695.
15. Wong AP, Nili N, Jackson ZS, et al. Expansive remodeling in venous bypass grafts: Novel implications for vein graft disease. Atherosclerosis, 2008, 196(2): 580-589.
16. Berard X, Déglise S, Alonso F, et al. Role of hemodynamic forces in the ex vivo arterialization of human saphenousveins. J Vasc Surg, 2013, 57(5): 1371-1382.
17. Ma L, Guan YQ, Du ZD. Salvianolic Acid B Down-regulates Matrix Metalloproteinase-9 Activity and Expression in Tumor Necrosis Factor-α-induced Human Coronary Artery Endothelial Cells. Chin Med J(Engl), 2015, 128(19): 2658-2663.
18. Yu YM, Lin HC, Chang WC. Carnosic acid prevents the migration of human aortic smooth muscle cells by inhibiting the activation and expression of matrix metalloproteinase-9. Br J Nutr, 2008, 100(4): 731-738.
19. Lee SO, Jeong YJ, Yu MH, et al. Wogonin suppresses TNF-alpha-induced MMP-9 expression by blocking the NF-kappaB activation via MAPK signaling pathways in human aortic smooth muscle cells. Biochem Biophys Res Commun, 2006, 351(1): 118-125.
20. Egi K, Conrad NE, Kwan J, et al. Inhibition of inducible nitric oxide synthase and superoxide production reduces matrix metalloproteinase-9 activity and restores coronary vasomotor function in rat cardiac allografts. Eur J Cardiothorac Surg, 2004, 26(2): 262-269.
21. Hayashi T, Matsui-Hirai H, Fukatsu A, et al. Selective iNOS inhibitor, ONO1714 successfully retards the development of high-cholesterol diet induced atherosclerosis by novel mechanism. Atherosclerosis, 2006, 187(2): 316-324.
22. Feng Y, Tang Y, Guo J, et al. Inhibition of LPS-induced TNF-alpha production by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. Life Sci, 1997, 61(20): PL281-PL287.

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Mosaic adeno-associated virus-mediated gene transfer of calcitonin gene-related peptide for prevention of inflammatory mediator expression, macrophage infiltration and neointimal hyperplasia in an experimental rabbit vein graft model

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