蝮蛇毒蛋白C激活物改善急性心肌梗死大鼠心功能的机制研究

中国临床药理学与治疗学 ›› 2012, Vol. 17 ›› Issue (2): 141-146.

蝮蛇毒蛋白C激活物改善急性心肌梗死大鼠心功能的机制研究

李曙¹, 张根葆^1,2, 洪云³, 陆晓华⁴

¹皖南医学院病理生理学教研室,
²皖南医学院蛇毒研究所,
³皖南医学院弋矶山医院超声医学科,
⁴皖南医学院机能实验中心,芜湖 241002,安徽

收稿日期:2011-10-26 修回日期:2012-01-11 出版日期:2012-02-26 发布日期:2012-03-12
通讯作者: 张根葆,男,教授,研究方向:心脑血管病理生理学。Tel: 0553-3932435 E-mail: zgb858@163.com
作者简介:李曙,男,博士在读,讲师,研究方向:生物毒素的提取和活性研究。Tel: 0553-3932476 E-mail: yxx2003@126.com
基金资助:
安徽省高等学校省级自然科学研究项目(KJ2010B461);安徽省科技厅科技项目(10021303009);皖南医学院中青年课题(WK200918)

Study on mechanisms of Agkistrodon halyx pallas venom PCA to improve heart function in rats with acute myocardial infarction

LI Shu¹, ZHANG Gen-bao^1,2, HONG Yun³, LU Xiao-hua⁴

¹Department of Pathophysiology,
²Institute of Snake Venom,
³Department of Ultrasonography, Yijishan Hospital,
⁴Experimental Center for Functional Subjects,Wannan Medical University,Wuhu 241002,Anhui,China

Received:2011-10-26 Revised:2012-01-11 Online:2012-02-26 Published:2012-03-12

摘要/Abstract

摘要： 目的: 探讨皖南产蝮蛇毒(AHV)蛋白C激活物(protein C activator,PCA)改善急性心肌梗死大鼠心功能作用与机制。方法: Sprague-Dawly大鼠60只,随机分为假手术(SH)组、心肌梗死模型(MI)组、PCA低、中、高剂量组(0.5、2、8 mg/kg)、阳性对照组(阿司匹林 5 mg/kg),每组10只。通过结扎冠状动脉前降支建立急性心肌梗死(AMI)模型,采用Medlab生物信号处理系统监测大鼠心脏血流动力学变化。Western blot检测心肌基质金属蛋白酶-9(MMP-9)蛋白表达;光镜观察心肌组织学改变。结果: 与心肌梗死组比较,PCA高、中剂量大鼠左室内压最低值(LVDP)、左心室舒张末期压(LVEDP)、左心室压力最大上升速率(+dp/dt_max) 、左心室压力最大下降速率(-dp/dt_max)明显升高(P＜0.05),MMP-9的蛋白表达下降(P＜0.05)。病理观察显示PCA干预组较梗死模型组炎症细胞浸润显著减轻,梗死面积缩小。结论: 蝮蛇毒PCA组分可以限制急性心肌梗死早期心肌梗死扩大,有效改善心脏血液动力学,抑制MMP-9表达,对急性心肌梗死后心室重构有一定的干预作用。

关键词: 蝮蛇毒, 蛋白C激活物, 心肌梗死, 心室重构, 基质金属蛋白酶

Abstract: AIM: To explore the effect of protein C activator(PCA) from Wannan Agkistrodon halyx pallas venom on heart function in rats with acute myocardial infarction and its mechanism.METHODS: Sixty SD rats were randomly divided into sham operation (SH)group, myocardial infarct(MI)group, low dose, medium dose and high dose of PCA groups (0.5,2,8 mg/kg) and aspirin group (5 mg/kg), and ten in each group. Through ligating of the anterior descending coronary artery to establish AMI,the cardiac muscle samples were obtained 12 hours after AMI. Medlab bio-signal processing system monitored hemodynamic changes in rat heart. The expression of myocardial MMP-9 was detected by Western blot.Myocardial cell and interstitial tissue were observed by microscope.RESULTS: Compared with myocardial infarct group rats, high dose and medium dose PCA significantly increased LVDP, LVEDP, significantly increased +dp/dt_max and -dp/dt_max and reduced levels of MMP-9 protein expression (P <0.05). Cardiac histological detection showed that PCA significantly reduced in infiltration of inflammatory cells and infarct size compared with AMI group.CONCLUSION: Agkistrodon halyx pallas venom PCA can limit the expansion of early myocardial infarction, improve cardiac hemodynamics, inhibit expression of MMP-9, so it would have a certain intervention effect on ventricular remodeling after acute myocardial infarction.

Key words: Agkistrodon halyx pallas venom, Protein C activator, Acute myocardial infarction, Ventricular remodeling, Matrix metalloproteinase

中图分类号:

R965.2

李曙, 张根葆, 洪云, 陆晓华. 蝮蛇毒蛋白C激活物改善急性心肌梗死大鼠心功能的机制研究[J]. 中国临床药理学与治疗学, 2012, 17(2): 141-146.

LI Shu, ZHANG Gen-bao, HONG Yun, LU Xiao-hua. Study on mechanisms of Agkistrodon halyx pallas venom PCA to improve heart function in rats with acute myocardial infarction[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(2): 141-146.

参考文献

[1] Visse R,Nagase H.Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure,function,and biochemistry[J].Circ Res,2003, 92(8):827-839.
[2] 张根葆,陈冬云,周志泳,等.蝮蛇毒蛋白C激活物的纯化与抗血小板活性[J]. 皖南医学院学报,2005, 24(1):8-10.
[3] Selye H,Bajusz E, Grasso S, et al.Simple techniques for the surgical occlusion of coronary artery vessels in the rat[J].Angiology,1960,11(5):398-407.
[4] Moon C,Krawczyk M,Paik D,et al.Cardioprotection by recombinant human erythropoietin following acute experimental myocardial infarction:dose response and therapeutic window[J]. Cardiovasc Drugs Ther,2005, 19(4):243-250.
[5] Bodh I.Ventricular remodeling after infarction and the extracellular collagen matrix:when is enough enough[J] ? Circulation,2003, 108(11):1395-1403.
[6] Jugdutt BI.Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways[J]. Curr Drug Targets Cardiovasc Hacmatol Disord,2003, 3(1):1-30.
[7] Stawowy P, Margetd C, Kallisch H, et al. Regulation of matrix metalloproteinase MT1-MMP-2 in cardiac fibroblasts by TGF-β1 involves furin-convertase[J]. Cardial Res,2005, 63(1):87-97.
[8] Gaertner R,Jacob MP,Prunier F,et al.The plasminogen MMP system is more activate dinthescarthan inviablemyo cardium months of MI in the rat[J]. J Mol Cell Cardiol,2005, 38(1):193-204.
[9] Wilson EM,Moainie SL,Baskin JM,et al.Region-and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling[J]. Circulation,2003, 107(22):2857-2863.
[10] Peterson TJ,Li H,Dillon L,et al.Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infracted rat[J].Cardiovasc Res,2000,46(2):307-315.
[11] Ducharme A,Frantz S,Aikawa M,et al.Targeted deletion of matrix metalloProteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction[J]. J Clin Invest,2000, 106(1):55-62.
[12] Mukherjee R,Brinsa TA,Dowdy KB,et al.Myocardial infarction expansion and matrix metalloproteinase inhibition[J]. Circulation, 2003, 107(4):618-625.
[13] Yarbrough WM,Mukherjee R,Brinsa TA,et al.Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs[J].J Thorac Cardiovasc Surg,2003, 125 (3):602-610.
[14] Yarbrough WM,Mukherjee R, Escobar GP, et al. Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling[J]. Circulation, 2003, 108 (14):1753-1759.
[15] 王伟, 牛凡 ,宋洁. 贝那普利及卡托普利对大鼠心肌梗死后心室重构及基质金属蛋白酶-2表达的影响[J]. 中西医结合心脑血管病杂志,2008, 6(3):294-297.
[16] 王海华,张根葆. 蝮蛇毒蛋白 C激活物对内毒素性离体大鼠心脏功能的影响[J]. 蛇志,2007,19(1):4-7.
[17] 金元玖, 李正信, 吴晓艳. 蛇毒纤溶酶对急性心肌梗死溶栓再通患者的心肌保护作用[J]. 血栓与止血学,2010,15(4):161-163.