NF-κB抑制剂—吡咯烷二硫代氨基甲酸盐（PDTC）对大鼠缺血性心肌损伤后心衰的防治研究
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摘要
研究背景和目的:
炎症反应在心血管疾病发生、发展中的作用越来越受到人们重视。在心肌严重缺血性损伤(如心肌梗死)中,伴随的炎症反应更是参与了心肌损伤、愈合、纤维化以及心功能损害的全过程。研究表明,核因子κB (nuclear factor-κB,NF-κB)在调节炎症反应中起着重要作用,它的激活可以增强多种炎性介质基因的表达,从而引起细胞和组织损伤。单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)是诱导慢性炎症发生的主要趋化因子,在NF-κB调节炎症反应中可能起到重要作用。本研究通过在不同时间点应用NF-κB抑制剂—吡咯烷二硫代氨基甲酸盐(pyrrolidine dithiocarbamate,PDTC),抑制缺血性损伤心肌的NF-κB激活,观察其对大鼠缺血性心肌损伤及继发心衰的影响,探讨其作用机制,为防治缺血性心肌损伤后心衰提供一条新的治疗途径,为今后合理使用NF-κB抑制剂提供实验依据。
方法:
1.给大鼠皮下注射大剂量异丙肾上腺素(isoprenaline,ISO)建立大鼠缺血性心肌损伤模型。
2.设立对照组、实验组、治疗1组、治疗2组。
3.利用免疫组化、RT-PCR及ELISA等方法检测PDTC对心肌NF-κB、MCP-1 mRNA表达的影响及对血清MCP-1水平的影响。
4.利用心脏彩超评估不同时间点应用PDTC对大鼠缺血性心肌损伤后心功能变化的影响,同时检测心肌病理形态学等变化情况。
结果:
1.利用大剂量(>85mg/Kg)的ISO对大鼠进行皮下注射,成功复制了缺血性心肌损伤动物模型。
2.不同时间点应用PDTC均能够有效抑制缺血性损伤心肌NF-κB的激活、下调心肌MCP-1 mRNA的表达及血清MCP-1水平(P<0.01)。
3.预防性应用PDTC能够减轻心肌炎症反应,减小心肌细胞损伤范围,实验第14天,治疗1组左室收缩末期内径(LVESD)较实验组减小(P<0.05),射血分数(EF)优于实验组(P<0.05);但缺血性心肌损伤发生后早期应用PDTC,实验组与治疗2组心肌坏死面积无明显差异,与实验组相比,治疗2组肉芽组织替代受损心肌组织延迟,心肌坏死边缘区毛细血管密度减低及心肌坏死区肌纤维母细胞浸润受抑制,室壁瘤发生增加,实验第28天,治疗2组LVESD增加更为明显(P<0.05),EF更低(P<0.01)。
结论:
1.预防性应用PDTC能够减轻大剂量ISO所造成的心肌缺血性损伤,但缺血性心肌损伤发生后早期应用PDTC则可能对心肌修复不利。
2.应用PDTC能够对心肌缺血性损伤后的心室扩张、心功能损害起到一定的防治作用,但可能存在时效性差异,总体来说其有益作用可能主要得益于在心肌损伤急性期对心肌细胞的保护作用。
3.以上作用的机制可能与PDTC抑制缺血性损伤心肌NF-κB的激活并进而下调MCP-1的表达、调控炎症反应密切相关。
Background and objective:
Inflammation is involved in the pathogenesis of cardiovascular diseases, especially in the ischemic heart disease, including cardiac infarction, by causing myocardial damage, engaging into healing and fibrosis, leading to progressive impairment of cardiac function. Nuclear factor (NF)-κB has an important role in regulating inflammatory responses, which augments the expression of various inflammatory factors, consequently leads to cardiac injury. Monocyte chemoattractant protein (MCP)-1 is one of major chemokines, which may play an important role in the NF-kB-mediated effects by inducing inflammation. In this experiment, we observed the effect of NF-κB inhibition, using a NF-kB inhibitor (pyrrolidine dithiocarbamate, PDTC), on cardiac injury by ischemia and subsequent heart failure, the mechanisms underlying the protective of PDTC were also investigated.
Methods:
1. The cardiac injury models were established by hypodermic injection of high dose of isoprenaline (ISO) in rats.
2. Rats were divided into control group, experimental group, treated group-1 and treated group-2.
3. The expressions of cardiac NF-kB, MCP-1 mRNA and the plasma MCP-l levels were checked by immunohistochemistry, RT-PCR and ELISA.
4. Cardiac function was determined by echocardiography, cardiac pathogenic states were also checked in this study.
Results :
1. The cardiac injury models were successfully established by hypodermic injection of high dose of isoprenaline (>85mg/kg ) in rats.
2. PDTC down-regulated myocardial NF-κB, MCP-1 mRNA expressions and plasma MCP-1 levels in both treated group-1 and treated group-2.
3. Pre-treatment with PDTC alleviated myocardial inflammation and injury. As compared with control, PDTC decreased left ventricular end-systolic dimension (LVESD), increased percentage of ejection fraction after treatment for 14 days. However, after occurrence of ischemic injury, the application of PDTC, even in the early stage, could not alleviate cardiac necrotic area. PDTC could delay the replacement of the damaged myocardium with granulation tissue, depress capillary density in the border area of necrosis and decrease myofibroblast accumulation in the zone of necrosis. The ratio of ventricular aneurysm formation in treated group-2 was higher than experimental group. On day 28, the left ventricular functions in treated group-2 were worse than that in experimental group.
Conclusions:
1. Pretreatment with PDTC decreases myocardial ischemic injury induced by high dosage of ISO in rats. However, after occurrence of ischemic injury, even in the early stage, application of PDTC is harmful to heart.
2. PDTC might have some protective effects on heart by alleviating ventricular dilatation and heart failure induced by myocardial ischemic injury in rats, the protective effects may vary due to chronergy. The protective effect is ascribed to the protection of cardiac myocytes in the early stage of cardiac injury.
3. The above-mentioned effects are related to the inhibitioin of myocardial NF-κB activity, myocardial MCP-1 mRNA expression and serum MCP-1 synthesis.
炎症反应在心血管疾病发生、发展中的作用越来越受到人们重视。在心肌严重缺血性损伤(如心肌梗死)中,伴随的炎症反应更是参与了心肌损伤、愈合、纤维化以及心功能损害的全过程。研究表明,核因子κB (nuclear factor-κB,NF-κB)在调节炎症反应中起着重要作用,它的激活可以增强多种炎性介质基因的表达,从而引起细胞和组织损伤。单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)是诱导慢性炎症发生的主要趋化因子,在NF-κB调节炎症反应中可能起到重要作用。本研究通过在不同时间点应用NF-κB抑制剂—吡咯烷二硫代氨基甲酸盐(pyrrolidine dithiocarbamate,PDTC),抑制缺血性损伤心肌的NF-κB激活,观察其对大鼠缺血性心肌损伤及继发心衰的影响,探讨其作用机制,为防治缺血性心肌损伤后心衰提供一条新的治疗途径,为今后合理使用NF-κB抑制剂提供实验依据。
方法:
1.给大鼠皮下注射大剂量异丙肾上腺素(isoprenaline,ISO)建立大鼠缺血性心肌损伤模型。
2.设立对照组、实验组、治疗1组、治疗2组。
3.利用免疫组化、RT-PCR及ELISA等方法检测PDTC对心肌NF-κB、MCP-1 mRNA表达的影响及对血清MCP-1水平的影响。
4.利用心脏彩超评估不同时间点应用PDTC对大鼠缺血性心肌损伤后心功能变化的影响,同时检测心肌病理形态学等变化情况。
结果:
1.利用大剂量(>85mg/Kg)的ISO对大鼠进行皮下注射,成功复制了缺血性心肌损伤动物模型。
2.不同时间点应用PDTC均能够有效抑制缺血性损伤心肌NF-κB的激活、下调心肌MCP-1 mRNA的表达及血清MCP-1水平(P<0.01)。
3.预防性应用PDTC能够减轻心肌炎症反应,减小心肌细胞损伤范围,实验第14天,治疗1组左室收缩末期内径(LVESD)较实验组减小(P<0.05),射血分数(EF)优于实验组(P<0.05);但缺血性心肌损伤发生后早期应用PDTC,实验组与治疗2组心肌坏死面积无明显差异,与实验组相比,治疗2组肉芽组织替代受损心肌组织延迟,心肌坏死边缘区毛细血管密度减低及心肌坏死区肌纤维母细胞浸润受抑制,室壁瘤发生增加,实验第28天,治疗2组LVESD增加更为明显(P<0.05),EF更低(P<0.01)。
结论:
1.预防性应用PDTC能够减轻大剂量ISO所造成的心肌缺血性损伤,但缺血性心肌损伤发生后早期应用PDTC则可能对心肌修复不利。
2.应用PDTC能够对心肌缺血性损伤后的心室扩张、心功能损害起到一定的防治作用,但可能存在时效性差异,总体来说其有益作用可能主要得益于在心肌损伤急性期对心肌细胞的保护作用。
3.以上作用的机制可能与PDTC抑制缺血性损伤心肌NF-κB的激活并进而下调MCP-1的表达、调控炎症反应密切相关。
Background and objective:
Inflammation is involved in the pathogenesis of cardiovascular diseases, especially in the ischemic heart disease, including cardiac infarction, by causing myocardial damage, engaging into healing and fibrosis, leading to progressive impairment of cardiac function. Nuclear factor (NF)-κB has an important role in regulating inflammatory responses, which augments the expression of various inflammatory factors, consequently leads to cardiac injury. Monocyte chemoattractant protein (MCP)-1 is one of major chemokines, which may play an important role in the NF-kB-mediated effects by inducing inflammation. In this experiment, we observed the effect of NF-κB inhibition, using a NF-kB inhibitor (pyrrolidine dithiocarbamate, PDTC), on cardiac injury by ischemia and subsequent heart failure, the mechanisms underlying the protective of PDTC were also investigated.
Methods:
1. The cardiac injury models were established by hypodermic injection of high dose of isoprenaline (ISO) in rats.
2. Rats were divided into control group, experimental group, treated group-1 and treated group-2.
3. The expressions of cardiac NF-kB, MCP-1 mRNA and the plasma MCP-l levels were checked by immunohistochemistry, RT-PCR and ELISA.
4. Cardiac function was determined by echocardiography, cardiac pathogenic states were also checked in this study.
Results :
1. The cardiac injury models were successfully established by hypodermic injection of high dose of isoprenaline (>85mg/kg ) in rats.
2. PDTC down-regulated myocardial NF-κB, MCP-1 mRNA expressions and plasma MCP-1 levels in both treated group-1 and treated group-2.
3. Pre-treatment with PDTC alleviated myocardial inflammation and injury. As compared with control, PDTC decreased left ventricular end-systolic dimension (LVESD), increased percentage of ejection fraction after treatment for 14 days. However, after occurrence of ischemic injury, the application of PDTC, even in the early stage, could not alleviate cardiac necrotic area. PDTC could delay the replacement of the damaged myocardium with granulation tissue, depress capillary density in the border area of necrosis and decrease myofibroblast accumulation in the zone of necrosis. The ratio of ventricular aneurysm formation in treated group-2 was higher than experimental group. On day 28, the left ventricular functions in treated group-2 were worse than that in experimental group.
Conclusions:
1. Pretreatment with PDTC decreases myocardial ischemic injury induced by high dosage of ISO in rats. However, after occurrence of ischemic injury, even in the early stage, application of PDTC is harmful to heart.
2. PDTC might have some protective effects on heart by alleviating ventricular dilatation and heart failure induced by myocardial ischemic injury in rats, the protective effects may vary due to chronergy. The protective effect is ascribed to the protection of cardiac myocytes in the early stage of cardiac injury.
3. The above-mentioned effects are related to the inhibitioin of myocardial NF-κB activity, myocardial MCP-1 mRNA expression and serum MCP-1 synthesis.
引文
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1 Andreotti F, Porto I, Crea F, et al. Inflammatory gene polymorphisms and ischemic heart disease: review of population association studies. Heart. 2002,87(2):107–112.
2 Ikeda U. Inflammation and coronary artery disease. Curr Vasc Pharmacol. 2003,1(1):65–70.
3 Ross R. Atherosclerosis: an inflammation disease. N Engl J Med. 1999,340(2):115–126.
4 Frangogiannis NG, Entman ML. Chemokines in myocardial ischemia. Trends Cardiovasc Med. 2005,15(5):163–169.
5 Becker LC. Yin and Yang of MCP-1. Circ Res. 2005,96(8):812–814.
6 Hayashidani S, Tsutsui H, Shiomi T, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2003,108(17):2134-2140.
7 Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol. 2001,2(2):108–115.
8 Ueda A, Okuda K, Ohno S, et al. NF-κB and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. J Immunol. 1994,153(5):2052–2063.
9 Damas JK, Aukrust P, Ueland T, et al. Monocyte chemoattractant protein-1 enhances and interleukin-10 suppresses the production of inflammatory cytokines in adult rat cardiomyocytes. Basic Res Cardiol. 2001,96(4):345-352.
10 Kolattukudy PE, Quach T, Bergese S, et al. Myocarditis induced by targeted expression of the MCP-1 gene in murine cardiac muscle. Am J Pathol. 1998,152(1):101-111.
11 Tonnessen T, Florholmen G, Henriksen UL, et al. Cardiopulmonary alterations in mRNA expression for interleukin-1beta, the interleukin-6 superfamily and CXC-chemokines during development of postischaemic heart failure in the rat. Clin-Physiol-Funct-Imaging. 2003,23(5):263-268.
12 Fuse K, Kodama M, Hanawa H, et al. Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis. Clin Exp Immunol. 2001,124(3):346–352.
13 Goser S, Ottl R, Brodner A, et al. Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy. Circulation. 2005,112(22):3400–3407.
14 Sigusch HH, Lehmann MH, Reinhardt D, et al. Chemotactic activity of serum obtained from patients with idiopathic dilated cardiomyopathy. Pharmazie. 2006,61(8):706-709.
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16 Damas JK, Eiken HG, Oie E, et al. Myocardial expression of CC- and CXC-chemokines and their receptors in human end-stage heart failure. Cardiovasc Res. 2000,47(4): 778-787.
17 Kaikita K, Hayasaki T, Okuma T, et al. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Am J Pathol. 2004,165(2):439–447.
18 Niu J, Azfer A, Deucher MF, et al. Targeted cardiac expression of soluble Fas prevents the development of heart failure in mice with cardiac-specific expression of MCP-1. J Mol Cell Cardiol. 2006,40(6):810-820.
19 Zhou L, Azfer A, Niu J, et al. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res. 2006,98(9):1177-1185.
20 Matsumoto Y, Tsukada Y, Miyakoshi A, et al. C protein-induced myocarditis and subsequent dilated cardiomyopathy: rescue from death and prevention of dilated cardiomyopathy by chemokine receptor DNA therapy. Immunol. 2004,173(5):3535-3541.
2 Ostuka G, Nagaya T, Saito K, et al. Inhibition of Nuclear factor-κB activation confers sensitivity to tumor necrosis factor-αby impairment of cell cycle progression in human glioma cells. Cancer Res. 1999,59(17):4446-4452.
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