Inhibition of Valproic acid on Rat Thoracic Aortic Aneurysm and Its Mechanism_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

TANGRui , GUTian-xiang , SHIEn-yi , WANGChun , ZHANGGuang-wei , MAONai-hui

Department of Cardiac Surgery of the First Affiliated Hospital of China Medical University, Shengyang 110001, P. R. China;

Corresponding?author：

Keywords：

Valproic acid; Inflammatory cells; Smooth muscle cells; Matrix metalloproteinases

DOI：

10.7507/1007-4848.20150147

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Objective To explore the inhibition action of valproic acid to inflammatory cells and smooth muscle cells then to find out that valproic acid (VPA) can repress rat thoracic aortic aneurysm or not. Methods The model of rat thoracic aortic aneurysm was built through the method of soaking the adventitia of artery using porcine pancreatic elastase (PPE). The rats were divided into three groups:a normal saline blank control group (a C group), an adventitia soaked PPE group (a P group), and adventitia soaked PPE plus intraperitoneal injection by injecting intraperitioneal VPA 200 mg/kg for seven days (a PV group).The animals of the three groups were all using vascular ultrasound to detect blood vessel diameter. Animals were killed after operation to observe the general morphology of vascular aneuysm and do the immunohistochemial, morphological, protein analysis of interleukin 1 (IL-1), interleukin 6 (IL-6), smooth muscle 22 alpha (SM22α), matrix metallopeptidase 2 (MMP-2), MMP-9 and Western blot by drawing animals on the 14th day. Results The vessels diameter in the PV group was narrower than that in the P group (P value<0.05). HE staining, immunohistochemistry and Western blot displayed that the cells in the P group were in disorder arrangement and interstitial disorder while the cells in the PV group maintained better albumin layer. The protein expressions of IL-1, IL-6, MMP-2, and MMP-9 in the PV group decreased except that SM22α increased. Conclusion VPA can inhibit phenothpic transforming of aneurysm inflammatory cells and smooth muscle cells, reduce the levels of cell proliferation, decrease the secretion of matrix metalloproteinases, and depress tumor growth of rat thoracic aorta.

Citation： TANGRui, GUTian-xiang, SHIEn-yi, WANGChun, ZHANGGuang-wei, MAONai-hui. Inhibition of Valproic acid on Rat Thoracic Aortic Aneurysm and Its Mechanism. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2015, 22(6): 578-584. doi: 10.7507/1007-4848.20150147 Copy

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3.	Ailawadi G, Eliason JL, Upchurch GR. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg, 2003, 38(3): 584-588.
4.	Kawai-Kowase K, Owens GK. Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells. Am J Physiol Cell Physiol, 2007, 292(1): C59-C69.
5.	Lesauskaite V, Epistolato MC, Castagnini M, et al. Expression of matrix metalloproteinases,their tissue inhibitors and osteopontin in the wall of thoracic and abdiminal aortas with dilatative pathology. J Hum Pathol, 2006, 37(8): 1076-1084.
6.	Vainas T, Lubbers T, Stassen FR, et al. Serum C-reactive protein level is associated with abdminal aortic aneurysm size and May be produced by aneurysmal tissue. J Circulation, 2003, 10(7): 1103-1105.
7.	Owens GK, Kumar MS,Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev, 2004, 84(3): 767-801.
8.	Li J, Li G, Xu W. Histone deacetylase inhibitors:an attractive strategy for cancer therapy. Curr Med Chem, 2013, 20(14): 1858-1886.
9.	Tang JH, Yan HD, Zhuang SG. Histone deacetylases as targets for treatment of multiple diseases. Clin Sci, 2013, 124(11/12): 651-662.
10.	Mcdonald OG, Wamhoff BR, Hoofnagle MH, et al. Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. J Clin Invest, 2006, 116(1): 36-48.
11.	Margariti A, Zampetaki A, Xiao QZ, et al. Histone deacetylase 7 controls endothelial cell growth through modulation of beta-Catenin. Circ Res, 2010, 106(7): 1U75-1202.
12.	Findeisen HM, Gizard F, Zhao YE, et al. Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition. Arterioscler Thromb Vasc Biol, 2011, 31(4): 851-U302.
13.	Suda S, Katsura KI, Kanamaru T, et al. Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation. Eur J Pharmacol, 2013, 707(1/3): 26-31.
14.	Bhamidipati CM, Mehta GS, Lu GY, et al. Development of a novel murine model of aortic aneurysms using peri-adventitial elastase. Surgery, 2012, 152(2): 238-246.
15.	Yuan SM, Jing H. Cystic medial necrosis: pathological findings and clinical implications. Rev Bras Cir Cardiovasc, 2011, 26(1): 107-115.
16.	Dietz HC, Cutting GR, Pyeritz RE,et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 1991, 352(6333): 337-339.
17.	Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular,craniofacial,neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet, 2005, 37: 275-281.
18.	Van de Laar IM, Oldenburg RA, Pals G, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet, 2011, 43: 121-126.
19.	Guo DC, Pannu H, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) Lead to thoracic aortic aneurysms and dissections. Nat Genet, 2007, 39(12): 1488-1493.
20.	Zhu LM, Vranckx R, Van Kien PK,et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet, 2006, 38(3): 343-349.
21.	Kuivaniemi H, Ryer EJ, Elmore JR, et al. Update on abdominal aortic aneurysm research: from clinical to genetic studies. Scientifica (Cairo), 2014: 564734.
22.	Schonbeck U, Sukhova GK, Gerdes N, et al. T(H)2 predominant immune responses prevail in human abdominal aortic aneurysm. Am J Pathol, 2002, 161: 499-506.
23.	Xiong WF, Zhao Y, Prall A, et al. Key roles of CD4(+) T cells and IFN-gamma in the development of abdominal aortic aneurysms in a murine model. J Immunol, 2004, 172(4): 2607-2612.
24.	Galle C, Schandene L, Stordeur P, et al. Predominance of type 1 CD4(+)T cells in human abdominal aortic aneurysm. Clin Exp Immunol, 2005, 142(3): 519-527.
25.	Lindeman JH, Abdul-Hussien H, Schaapherder AF, et al. Enhanced expression and activationofpro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm. Clin Sci (Lond), 2008,114:687-97.
26.	Toumpoulis IK, Oxford JT, Cowan DB, et al. Differential expression of collagen type V and XI alpha-1 in human ascending thoracic aortic aneurysms. Arterioscler Thromb Vasc Biol, 2009, 29(7): E119.
27.	Ghosh AK, Quaggin SE,Vaughan DE. Molecular basis of organ fibrosis: Potential therapeutic approaches. Exp Biol Med, 2013, 238(5): 461-481.
28.	Ikonomidis JS, Gibson WC, Gardner J, et al. A murine model of thoracic aortic aneurysms. J Surg Res, 2003, 115(1): 157-163.

1. ?Wu D, Shen Yh, Russell L,et al. Molecular mechanisms of thoracic aortic dissection. J Surg Res,2013,184(2): 907-924.
2. Kochanek KD, Xu J, Murphy SL, et al. Deaths: final data for 2009. Natl Vital Stat Rep, 2011, 60(3): 1-116.
3. Ailawadi G, Eliason JL, Upchurch GR. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg, 2003, 38(3): 584-588.
4. Kawai-Kowase K, Owens GK. Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells. Am J Physiol Cell Physiol, 2007, 292(1): C59-C69.
5. Lesauskaite V, Epistolato MC, Castagnini M, et al. Expression of matrix metalloproteinases,their tissue inhibitors and osteopontin in the wall of thoracic and abdiminal aortas with dilatative pathology. J Hum Pathol, 2006, 37(8): 1076-1084.
6. Vainas T, Lubbers T, Stassen FR, et al. Serum C-reactive protein level is associated with abdminal aortic aneurysm size and May be produced by aneurysmal tissue. J Circulation, 2003, 10(7): 1103-1105.
7. Owens GK, Kumar MS,Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev, 2004, 84(3): 767-801.
8. Li J, Li G, Xu W. Histone deacetylase inhibitors:an attractive strategy for cancer therapy. Curr Med Chem, 2013, 20(14): 1858-1886.
9. Tang JH, Yan HD, Zhuang SG. Histone deacetylases as targets for treatment of multiple diseases. Clin Sci, 2013, 124(11/12): 651-662.
10. Mcdonald OG, Wamhoff BR, Hoofnagle MH, et al. Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. J Clin Invest, 2006, 116(1): 36-48.
11. Margariti A, Zampetaki A, Xiao QZ, et al. Histone deacetylase 7 controls endothelial cell growth through modulation of beta-Catenin. Circ Res, 2010, 106(7): 1U75-1202.
12. Findeisen HM, Gizard F, Zhao YE, et al. Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition. Arterioscler Thromb Vasc Biol, 2011, 31(4): 851-U302.
13. Suda S, Katsura KI, Kanamaru T, et al. Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation. Eur J Pharmacol, 2013, 707(1/3): 26-31.
14. Bhamidipati CM, Mehta GS, Lu GY, et al. Development of a novel murine model of aortic aneurysms using peri-adventitial elastase. Surgery, 2012, 152(2): 238-246.
15. Yuan SM, Jing H. Cystic medial necrosis: pathological findings and clinical implications. Rev Bras Cir Cardiovasc, 2011, 26(1): 107-115.
16. Dietz HC, Cutting GR, Pyeritz RE,et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 1991, 352(6333): 337-339.
17. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular,craniofacial,neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet, 2005, 37: 275-281.
18. Van de Laar IM, Oldenburg RA, Pals G, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet, 2011, 43: 121-126.
19. Guo DC, Pannu H, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) Lead to thoracic aortic aneurysms and dissections. Nat Genet, 2007, 39(12): 1488-1493.
20. Zhu LM, Vranckx R, Van Kien PK,et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet, 2006, 38(3): 343-349.
21. Kuivaniemi H, Ryer EJ, Elmore JR, et al. Update on abdominal aortic aneurysm research: from clinical to genetic studies. Scientifica (Cairo), 2014: 564734.
22. Schonbeck U, Sukhova GK, Gerdes N, et al. T(H)2 predominant immune responses prevail in human abdominal aortic aneurysm. Am J Pathol, 2002, 161: 499-506.
23. Xiong WF, Zhao Y, Prall A, et al. Key roles of CD4(+) T cells and IFN-gamma in the development of abdominal aortic aneurysms in a murine model. J Immunol, 2004, 172(4): 2607-2612.
24. Galle C, Schandene L, Stordeur P, et al. Predominance of type 1 CD4(+)T cells in human abdominal aortic aneurysm. Clin Exp Immunol, 2005, 142(3): 519-527.
25. Lindeman JH, Abdul-Hussien H, Schaapherder AF, et al. Enhanced expression and activationofpro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm. Clin Sci (Lond), 2008,114:687-97.
26. Toumpoulis IK, Oxford JT, Cowan DB, et al. Differential expression of collagen type V and XI alpha-1 in human ascending thoracic aortic aneurysms. Arterioscler Thromb Vasc Biol, 2009, 29(7): E119.
27. Ghosh AK, Quaggin SE,Vaughan DE. Molecular basis of organ fibrosis: Potential therapeutic approaches. Exp Biol Med, 2013, 238(5): 461-481.
28. Ikonomidis JS, Gibson WC, Gardner J, et al. A murine model of thoracic aortic aneurysms. J Surg Res, 2003, 115(1): 157-163.

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Inhibition of Valproic acid on Rat Thoracic Aortic Aneurysm and Its Mechanism

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