N-乙酰半胱氨酸對大鼠心臟移植缺血再灌注損傷細胞凋亡的影響_《中國修復重建外科雜志》

作者：

伊雪 ¹ , 崔翔宇 ² , 鄔鵬宇 ² , 王帥 ² , 王耕野 ² , 楊學慧 ² , 楊方 ¹ , 鄭素琴 ¹ , 李占清 ²

1 河北聯合大學基礎醫學院病理系（河北唐山，063000）;;
2河北聯合大學附屬醫院心胸外科;

關鍵詞：

心臟移植 N-乙酰半胱氨酸缺血再灌注損傷細胞凋亡大鼠

DOI：

10.7507/1002-1892.20130270

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目的觀察N-乙酰半胱氨酸（N-acetylcysteine，NAC）對大鼠心臟移植后心肌缺血再灌注損傷導致的細胞凋亡的影響，并探討其可能機制。方法健康雄性Lewis大鼠60只，體重200～220 g，隨機分為3組，每組20只，供、受體各10只。對照組：摘取供心前30 min經供體大鼠下腔靜脈注射生理鹽水1 mL；供體預處理組：摘取供心前30 min經供體大鼠下腔靜脈注射NAC（300 mg/kg），受體不作處理；受體預處理組：于移植前30 min經受體大鼠下腔靜脈注射NAC（300 mg/kg），供體不作處理。各組均建立同種異體異位心臟移植模型。術后觀察受體大鼠存活情況；于移植后6、24 h取靜脈血檢測天冬氨酸轉氨酶（aspartate aminotransferase，AST）、丙氨酸轉氨酶（alanine aminotransferase，ALT）、乳酸脫氫酶（lactate dehydrogenase，LDH）含量；移植后24 h，取心肌組織檢測超氧化物歧化酶（superoxide dismutase，SOD）、脂質過氧化物（lipid hydroperoxide，LPO）活性，觀察心肌組織學及超微結構，免疫組織化學染色檢測活性半胱氨酸天冬氨酸蛋白酶3（active Caspase-3）蛋白表達，TUNEL法檢測心肌細胞凋亡指數（apoptosis index，AI）。結果各組心臟移植手術均成功，大鼠均存活至實驗完成。移植后6 h，供、受體預處理組AST、ALT、LDH均顯著低于對照組（P lt; 0.05），24 h時供體預處理組AST、ALT及受體預處理組AST、LDH低于對照組（P lt; 0.05）；供、受體預處理組間各指標比較差異均無統計學意義（P gt; 0.05）。移植后6、24 h組內比較，除受體預處理組ALT差異無統計學意義外（P gt; 0.05）外，移植后24 h兩組各指標均顯著低于6 h（P lt; 0.05）。供、受體預處理組心肌組織中SOD含量及SOD/LPO均高于對照組（P lt; 0.05），供、受體預處理組比較差異無統計學意義（P gt; 0.05）；各組LPO比較差異均無統計學意義（P gt; 0.05）。組織學及透射電鏡觀察顯示，受體預處理組心肌損傷程度均明顯輕于對照組和供體預處理組；受體預處理組active Caspase-3蛋白表達量顯著高于對照組和供體預處理組（P lt; 0.05）；供、受體預處理組AI顯著低于對照組（P lt; 0.05），供、受體預處理組間差異無統計學意義（P gt; 0.05）。結論 NAC可以通過提高心肌SOD含量、降低active Caspase-3活性抑制心肌細胞凋亡來減輕大鼠心臟移植缺血再灌注損傷，進而保護供體心臟。

引用本文： 伊雪,崔翔宇,鄔鵬宇,王帥,王耕野,楊學慧,楊方,鄭素琴,李占清. N-乙酰半胱氨酸對大鼠心臟移植缺血再灌注損傷細胞凋亡的影響. 中國修復重建外科雜志, 2013, 27(10): 1234-1239. doi: 10.7507/1002-1892.20130270 復制

1.	Keck BM, White R, Breen TJ, et al. Thoracic organ transplants in the United States: a report from the UNOS/ISHLT scientific registry for organ transplants. United network for organ sharing. International society for heart and lung transplantation. Clin Transpl, 1994: 37-46.
2.	Orogo AM, Gustafsson AB. Cell death in the myocardium: My heart won’t go on. IUBMB Life, 2013, 65(8): 651-656.
3.	Kizilgun M, Poyrazoglu Y, Oztas Y, et al. Beneficial effects of N-acetylcysteine and ebselen on renal ischemia reperfusion injury. Ren Fail, 2011, 33(5): 512-517.
4.	Ono K, Lindsey ES. Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg, 1969, 57(2): 225-229.
5.	Poston RS, Ennen M, Pollard J, et al. Ex vivo gene therapy prevents chronic graft vascular disease in cardiac allografts. J Thorac Cardiovasc Surg, 1998, 116(3): 386-96.
6.	Jacobs TW, Gown AM, Yaziji H, et al. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol, 1999, 17(7): 1974-1982.
7.	Aune SE, Yeh ST, Zelinski DP, et al. Measurement of hydrogen peroxide and oxidant stress in a recirculating whole blood-perfused rat heart model. Resuscitation, 2011, 82(2): 222-227.
8.	Ling H, Gray CB, Zambon AC, et al. Ca2+/Calmodulin-dependent protein kinase II δ mediates myocardial ischemia/reperfusion injury through nuclear factor-κB. Circ Res, 2013, 112(6): 935-944.
9.	Kalogeris T, Baines CP, Krenz M, et al. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol, 2012, 298: 229-317.
10.	張川海, 陶貴周. N-乙酰半胱氨酸對家兔缺血再灌注損傷心肌細胞凋亡的影響. 山東醫藥, 2013, 53(2): 13-15.
11.	Li Z, Nickkholgh A, Yi X, et al. Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-κB and apoptosis after experimental kidney transplantation. J Pineal Res, 2009, 46(4): 365-372.
12.	李占清, 崔翔宇, 伊雪, 等. N-乙酰半胱氨酸對大鼠心臟移植缺血再灌注損傷的保護作用. 中華實驗外科雜志, 2013, 30(5): 995-998.
13.	Samuni Y, Goldstein S, Dean OM. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta, 2013, 1830(8): 4117-4129.
14.	聶紅霞, 唐偉敬, 齊共海, 等. N-乙酰半胱氨酸在心血管疾病中的應用進展. 中國心血管病研究雜志, 2010, 8(4): 316-319.
15.	Zu L, Zheng X, Wang B, et al. Ischemic preconditioning attenuates mitochondrial localization of PTEN induced by ischemia-reperfusion. Am J Physiol Heart Circ Physiol, 2011, 300(6): H2177-2186.
16.	Wu B, Lin R, Dai R, et al. Valsartan attenuates oxidative stress and NF-κB activation and reduces myocardial apoptosis after ischemia and reperfusion. Eur J Pharmacol, 2013, 705(1-3): 140-147.
17.	褚萬立, 柴家科, 馮永強, 等. 內質網應激反應在嚴重燒傷大鼠心肌細胞凋亡中的作用. 中國修復重建外科雜志, 2012, 26(5): 592-596.
18.	Toldo S, Breckenridge DG, Mezzaroma E, et al. Inhibition of apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion injury in the mouse. J Am Heart Assoc, 2012, 1(5): e002360.
19.	王雅坤, 鄭玉云, 張昕. 線粒體與心肌缺血-再灌注損傷及他汀類藥物的保護作用. 中華臨床醫師雜志(電子版), 2011, 5(22): 6684-6687.
20.	李延宏, 楊同群, 王秉義, 等. 17β-雌二醇對去勢大鼠慢性脊髓損傷后神經保護作用的實驗研究. 中國修復重建外科雜志, 2013, 27(6): 720-725.
21.	Gottlieb RA. Cell death pathways in acute ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther, 2011, 16(3-4): 233-238.
22.	Gómez-Crisóstomo NP, López-Marure R, Zapata E. Bax induces cytochrome c release by multiple mechanisms in mitochondria from MCF7 cells. J Bioenerg Biomembr, 2013, 45(5): 441-448.
23.	Choi YW, Park TJ, Kim HS. Signals regulating necrosis of cardiomyoblast by BTG2 (/TIS21/PC3) via activation of GSK3β and opening of mitochondrial permeability transition pore in response to H2O2. Biochem Biophys Res Commun, 2013, 434(3): 559-565.
24.	Kunduzova OR, Escourrou G, De La Farge F, et al. Involvement of peripheral benzodiazepine receptor in the oxidative stress, death-signaling pathways, and renal injury induced by ischemiare perfusion. J Am Soc Nephrol, 2004, 15(8): 2152-2160.
25.	Alizadeh AM, Faghihi M, Khori V, et al. Oxytocin protects cardiomyocytes from apoptosis induced by ischemia-reperfusion in rat heart: role of mitochondrial ATP-dependent potassium channel and permeability transition pore. Peptides, 2012, 36(1): 71-77.

1. Keck BM, White R, Breen TJ, et al. Thoracic organ transplants in the United States: a report from the UNOS/ISHLT scientific registry for organ transplants. United network for organ sharing. International society for heart and lung transplantation. Clin Transpl, 1994: 37-46.
2. Orogo AM, Gustafsson AB. Cell death in the myocardium: My heart won’t go on. IUBMB Life, 2013, 65(8): 651-656.
3. Kizilgun M, Poyrazoglu Y, Oztas Y, et al. Beneficial effects of N-acetylcysteine and ebselen on renal ischemia reperfusion injury. Ren Fail, 2011, 33(5): 512-517.
4. Ono K, Lindsey ES. Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg, 1969, 57(2): 225-229.
5. Poston RS, Ennen M, Pollard J, et al. Ex vivo gene therapy prevents chronic graft vascular disease in cardiac allografts. J Thorac Cardiovasc Surg, 1998, 116(3): 386-96.
6. Jacobs TW, Gown AM, Yaziji H, et al. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol, 1999, 17(7): 1974-1982.
7. Aune SE, Yeh ST, Zelinski DP, et al. Measurement of hydrogen peroxide and oxidant stress in a recirculating whole blood-perfused rat heart model. Resuscitation, 2011, 82(2): 222-227.
8. Ling H, Gray CB, Zambon AC, et al. Ca2+/Calmodulin-dependent protein kinase II δ mediates myocardial ischemia/reperfusion injury through nuclear factor-κB. Circ Res, 2013, 112(6): 935-944.
9. Kalogeris T, Baines CP, Krenz M, et al. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol, 2012, 298: 229-317.
10. 張川海, 陶貴周. N-乙酰半胱氨酸對家兔缺血再灌注損傷心肌細胞凋亡的影響. 山東醫藥, 2013, 53(2): 13-15.
11. Li Z, Nickkholgh A, Yi X, et al. Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-κB and apoptosis after experimental kidney transplantation. J Pineal Res, 2009, 46(4): 365-372.
12. 李占清, 崔翔宇, 伊雪, 等. N-乙酰半胱氨酸對大鼠心臟移植缺血再灌注損傷的保護作用. 中華實驗外科雜志, 2013, 30(5): 995-998.
13. Samuni Y, Goldstein S, Dean OM. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta, 2013, 1830(8): 4117-4129.
14. 聶紅霞, 唐偉敬, 齊共海, 等. N-乙酰半胱氨酸在心血管疾病中的應用進展. 中國心血管病研究雜志, 2010, 8(4): 316-319.
15. Zu L, Zheng X, Wang B, et al. Ischemic preconditioning attenuates mitochondrial localization of PTEN induced by ischemia-reperfusion. Am J Physiol Heart Circ Physiol, 2011, 300(6): H2177-2186.
16. Wu B, Lin R, Dai R, et al. Valsartan attenuates oxidative stress and NF-κB activation and reduces myocardial apoptosis after ischemia and reperfusion. Eur J Pharmacol, 2013, 705(1-3): 140-147.
17. 褚萬立, 柴家科, 馮永強, 等. 內質網應激反應在嚴重燒傷大鼠心肌細胞凋亡中的作用. 中國修復重建外科雜志, 2012, 26(5): 592-596.
18. Toldo S, Breckenridge DG, Mezzaroma E, et al. Inhibition of apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion injury in the mouse. J Am Heart Assoc, 2012, 1(5): e002360.
19. 王雅坤, 鄭玉云, 張昕. 線粒體與心肌缺血-再灌注損傷及他汀類藥物的保護作用. 中華臨床醫師雜志(電子版), 2011, 5(22): 6684-6687.
20. 李延宏, 楊同群, 王秉義, 等. 17β-雌二醇對去勢大鼠慢性脊髓損傷后神經保護作用的實驗研究. 中國修復重建外科雜志, 2013, 27(6): 720-725.
21. Gottlieb RA. Cell death pathways in acute ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther, 2011, 16(3-4): 233-238.
22. Gómez-Crisóstomo NP, López-Marure R, Zapata E. Bax induces cytochrome c release by multiple mechanisms in mitochondria from MCF7 cells. J Bioenerg Biomembr, 2013, 45(5): 441-448.
23. Choi YW, Park TJ, Kim HS. Signals regulating necrosis of cardiomyoblast by BTG2 (/TIS21/PC3) via activation of GSK3β and opening of mitochondrial permeability transition pore in response to H2O2. Biochem Biophys Res Commun, 2013, 434(3): 559-565.
24. Kunduzova OR, Escourrou G, De La Farge F, et al. Involvement of peripheral benzodiazepine receptor in the oxidative stress, death-signaling pathways, and renal injury induced by ischemiare perfusion. J Am Soc Nephrol, 2004, 15(8): 2152-2160.
25. Alizadeh AM, Faghihi M, Khori V, et al. Oxytocin protects cardiomyocytes from apoptosis induced by ischemia-reperfusion in rat heart: role of mitochondrial ATP-dependent potassium channel and permeability transition pore. Peptides, 2012, 36(1): 71-77.

《中國修復重建外科雜志》

N-乙酰半胱氨酸對大鼠心臟移植缺血再灌注損傷細胞凋亡的影響

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《中國修復重建外科雜志》

N-乙酰半胱氨酸對大鼠心臟移植缺血再灌注損傷細胞凋亡的影響

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