Intermedin_（1-53）抗大鼠心肌纤维化作用及其机制研究
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摘要
目的心肌纤维化是多种心脏疾病发展到一定阶段的共同病理改变,是心室重构的主要表现之一。作为心血管活性肽类物质Intermedin1-53(IMD1-53)在改善心脏功能、抗心肌缺血/再灌注损伤等心血管疾病中发挥重要作用。但它是否具有抗心肌纤维化的作用及其作用机制尤其是信号转导方面机制尚未清楚。因此本课题以心肌成纤维细胞为靶点细胞,从体内外两方面观察IMD1-53抗心肌纤维化作用及信号转导机制。方法1.采用结扎大鼠左冠状动脉前降支诱导心肌纤维化动物模型,假手术组只穿线不结扎。4周后检测心功能;HE染色、天狼星红染色切片观察心肌形态学变化;Western blot方法检测Ⅰ、Ⅲ型胶原蛋白表达;RT-PCR、Western blot方法检测左室非梗死区心肌IMD1-53、降钙受体样受体(calcitonin receptor-like receptor,CRLR)、受体活性修饰蛋白(receptor-activity-modifying protein,RAMP)1/2/3基因和蛋白表达水平;通过放免法检测血浆和左室非梗死区心肌的醛固酮含量,RT-PCR方法检测左室非梗死区心肌组织醛固酮合成酶(CYP11B2)基因表达。2.以新生SD大鼠心肌成纤维细胞(cardiac fibroblast, CFb)为研究对象,醛固酮(aldosterone,ALD)诱导增殖。采用MTT法观察ALD对CFb增殖活性的影响;检测细胞上清液中羟脯氨酸含量分析IMD1-53是否具有抗ALD诱导CFb增殖的作用,以及用同样方法观察IMD1-53的同家系肾上腺髓质素(adrenomedullin,ADM)受体拮抗剂ADM22-52和降钙素基因相关肽(calcitonin gene-related peptide,CGRP)受体拮抗剂CGRP8-37是否可以抑制IMD1-53降低CFb增殖的作用;通过Western blot方法观察IMD1-53对ALD诱导的CFb的p-ERK1/2蛋白表达的影响。结果1.结扎大鼠左冠状动脉前降支4周可形成心肌纤维化动物模型。测定结果显示:与假手术组比较,模型组大鼠的心功能明显降低(P<0.01~0.05);天狼星红染色发现心肌纤维化明显增强;左室非梗死区心肌组织的Ⅰ、Ⅲ型胶原蛋白表达增加(P<0.05);左室非梗死区心肌IMD1-53,CL、RAMP1/2/3的mRNA表达水平分别上调75%(P<0.01),57%(P<0.05), 61%(P<0.01), 48%(P<0.05)和80%(P<0.05),左室非梗死区心肌CL、RAMP1/2/3蛋白表达水平分别上调108%、79%、80%和111% (P<0.01~0.05);血浆和左室非梗死区心肌组织中醛固酮含量分别升高了1.32倍(P<0.01)和3.14倍(P<0.01)。左室非梗死区心肌组织CYP11B2 mRNA表达增加了44%(P<0.05)。2. ALD可诱导CFb增殖。测定结果显示:与对照组比较,ALD刺激CFb 24h后,在ALD浓度为10-8~10-6mol/L范围内,可促CFb增殖(P<0.01~0.05),以ALD浓度为10-6mol/L时CFb MTT产物的OD值最大(P<0.01);IMD1-53可抑制ALD诱导的CFb增殖,检测羟脯氨酸(Hyp)含量明显降低,且呈剂量依赖性,与ALD组比较有显著性差异(P<0.01~0.05);ADM22-52和CGRP8-37均可减弱IMD1-53对ALD的作用;ALD可诱导CFb的p-ERK蛋白表达,ALD作用5 min,p-ERK蛋白表达开始升高,作用10 min,p-ERK蛋白表达达最高值;与对照组比较,IMD1-53可抑制ALD诱导的CFb的p-ERK蛋白的表达(P<0.05)。结论1.结扎大鼠左冠状动脉前降支4周可形成心肌纤维化动物模型;心肌纤维化大鼠心室肌IMD1-53,CRLR、RAMP1/2/3的mRNA及蛋白表达水平分别上调,血浆和心肌组织中醛固酮含量分别升高,CYP11B2 mRNA表达明显上调。2. ALD对CFb活力的影响在一定时间和一定的浓度范围内呈现增加趋势;IMD1-53在一定时间和一定的浓度范围内可以抑制ALD诱导的新生大鼠CFb的增殖;ADM的受体拮抗剂ADM22-52和CGRP的受体拮抗剂CGRP8-37均可减弱IMD1-53抑制CFb增殖的作用,提示IMD1-53可通过CGRP和ADM受体起作用抑制CFb增殖;ALD可激活细胞内p-ERK这一与细胞增殖密切相关的信号物质,IMD1-53能有效抑制ALD介导的p-ERK表达,提示IMD1-53可通过ERK信号通路抑制ALD诱导的CFb增殖从而改善心肌纤维化。
Objective Myocardial fibrosis is co-pathology change of many heart diseases,and one of major components of ventricular remodeling after MI. IMD1-53, Cardiac and vasoactive peptide, has impoitant effect on improving cardiac function, against ischemia-reperfusion injury.But there is no evidence that IMD1-53 have the effect on myocardial fibrosis and possible mechanism,especially, signal transduction mechanism.The topic observed IMD1-53 against myocardial fibrosis and possible signal transduction mechanism by developing animal models involved in vivo and vitro and propose to elucidate myocardial fibrosis mechanism.
Method 1. Rats with myocardial fibrosis(MF) were induced by left anterior descending coronary branch ligation. The cardiac function was messured , the protein levels of typeⅠ、Ⅲcollagen were assayed by Western blotting and the mRNA levels and the protein levels of IMD1-53, CL, RAMP1, -2, -3 were determined by semi-quantitative RT-PCR and Western blotting in the infracted hearts after 4 weeks of operation. ALD levels of plasma and myocardium region were messured by radioimmunity(RI). The mRNA levels of CYP11B2 were determined by semi-quantitative RT-PCR. 2. CFs from neonatal rat were separated,cultured ,and measured the CFb viability With MTT method after irritating with ALD; Observing IMD1-53 whether or not can inhibit CFs proliferation reduced by ALD with measuring the content of hydroxyproline(Hyp); Observing receptor antagonist of ADM and CGRP,the same fimily of IMD1-53, ADM22-52 and CGRP8-37 if or not have antagonism effect on IMD1-53 receptor with measuring the content of Hyp; We using measued of Western blot observed IMD1-53 if or not can inhibit the p-ERK expression reduced by ALD. Results 1 Myocardial fibrosis (MF) were formed by left anterior descending coronary branch ligation of 4 weeks.Compared with the sham-operated group, cardiac function was decreased (P<0.01~0.05);protein levels of typeⅠ、Ⅲcollagen were increased (P<0.05);the mRNA levels of CL, RAMP1, RAMP2 and RAMP3 were elevated by 75% (P<0.01), 57% (P<0.05), 61% (P<0.01), 48% (P<0.05)and 108% (P<0.05),protein levels of CL, RAMP1, RAMP2 and RAMP3 were elevated by 108%、79%、80%和111% (P<0.01~0.05) in the myocardial fibrosis rat. ALD levels of plasma and myocardium region were elevated separately 132%(P< 0.01),314%(P < 0.01). The mRNA levels of CYP11B2 were elevated by 44% (P<0.05). 2 ALD can reduce CFb proliferation. Compared with control group, ALD caused a concentration-dependent(10-8~10-6mol/L)increase of CFbs viability significantly in 24 hours and the peak of OD at concentration of 10-6mol/l ALD; IMD1-53 caused a concentration-dependent(10-9~10-7mol/L)decrease of CFs reduced by CFb and the Hyp content of cell supernatant decreased significantly, compared with control(P<0.01~0.05). ADM22-52 and CGRP8-37 can both inhibit IMD1-53. Western blotting results showed that p-ERK expression gradually increased after stimulating CFb with ALD from 5min to 10 min and decreasing from 10min~30min,with a peak at 10 min,with marked difference from control group. IMD can inhibit p-ERK expression of CFs reduced by ALD, with measuring the content of Hyp. Conclusion 1. MF were formed by left anterior descending coronary branch ligation of 4 weeks.The proteins and genes of IMD1-53 and receptors in myocardial fibrosis rat were obviously up-regulation in ventricular myocardium of Myocardial fibrosis rat. ALD levels of plasma and myocardium region were elevated separately. 2. ALD can increase CFb proliferation viability in concentration-dependent; IMD1-53 can inhibit CFb proliferation in a concentration-dependent reduced by ALD; ADM22-52 and CGRP8-37 can both inhibit the effect of IMD1-53 on ALD, it suggests that ADM22-52 and CGRP8-37 can antagonize IMD1-53 receptor;ALD can activate ERK signal transduction path. IMD1-53can inhibit p-ERK expression reduced by ALD, it suggests that IMD1-53 can inhibit CFs proliferation by ERK signal transduction path with the result of improving myocardial fibrosis.
Objective Myocardial fibrosis is co-pathology change of many heart diseases,and one of major components of ventricular remodeling after MI. IMD1-53, Cardiac and vasoactive peptide, has impoitant effect on improving cardiac function, against ischemia-reperfusion injury.But there is no evidence that IMD1-53 have the effect on myocardial fibrosis and possible mechanism,especially, signal transduction mechanism.The topic observed IMD1-53 against myocardial fibrosis and possible signal transduction mechanism by developing animal models involved in vivo and vitro and propose to elucidate myocardial fibrosis mechanism.
Method 1. Rats with myocardial fibrosis(MF) were induced by left anterior descending coronary branch ligation. The cardiac function was messured , the protein levels of typeⅠ、Ⅲcollagen were assayed by Western blotting and the mRNA levels and the protein levels of IMD1-53, CL, RAMP1, -2, -3 were determined by semi-quantitative RT-PCR and Western blotting in the infracted hearts after 4 weeks of operation. ALD levels of plasma and myocardium region were messured by radioimmunity(RI). The mRNA levels of CYP11B2 were determined by semi-quantitative RT-PCR. 2. CFs from neonatal rat were separated,cultured ,and measured the CFb viability With MTT method after irritating with ALD; Observing IMD1-53 whether or not can inhibit CFs proliferation reduced by ALD with measuring the content of hydroxyproline(Hyp); Observing receptor antagonist of ADM and CGRP,the same fimily of IMD1-53, ADM22-52 and CGRP8-37 if or not have antagonism effect on IMD1-53 receptor with measuring the content of Hyp; We using measued of Western blot observed IMD1-53 if or not can inhibit the p-ERK expression reduced by ALD. Results 1 Myocardial fibrosis (MF) were formed by left anterior descending coronary branch ligation of 4 weeks.Compared with the sham-operated group, cardiac function was decreased (P<0.01~0.05);protein levels of typeⅠ、Ⅲcollagen were increased (P<0.05);the mRNA levels of CL, RAMP1, RAMP2 and RAMP3 were elevated by 75% (P<0.01), 57% (P<0.05), 61% (P<0.01), 48% (P<0.05)and 108% (P<0.05),protein levels of CL, RAMP1, RAMP2 and RAMP3 were elevated by 108%、79%、80%和111% (P<0.01~0.05) in the myocardial fibrosis rat. ALD levels of plasma and myocardium region were elevated separately 132%(P< 0.01),314%(P < 0.01). The mRNA levels of CYP11B2 were elevated by 44% (P<0.05). 2 ALD can reduce CFb proliferation. Compared with control group, ALD caused a concentration-dependent(10-8~10-6mol/L)increase of CFbs viability significantly in 24 hours and the peak of OD at concentration of 10-6mol/l ALD; IMD1-53 caused a concentration-dependent(10-9~10-7mol/L)decrease of CFs reduced by CFb and the Hyp content of cell supernatant decreased significantly, compared with control(P<0.01~0.05). ADM22-52 and CGRP8-37 can both inhibit IMD1-53. Western blotting results showed that p-ERK expression gradually increased after stimulating CFb with ALD from 5min to 10 min and decreasing from 10min~30min,with a peak at 10 min,with marked difference from control group. IMD can inhibit p-ERK expression of CFs reduced by ALD, with measuring the content of Hyp. Conclusion 1. MF were formed by left anterior descending coronary branch ligation of 4 weeks.The proteins and genes of IMD1-53 and receptors in myocardial fibrosis rat were obviously up-regulation in ventricular myocardium of Myocardial fibrosis rat. ALD levels of plasma and myocardium region were elevated separately. 2. ALD can increase CFb proliferation viability in concentration-dependent; IMD1-53 can inhibit CFb proliferation in a concentration-dependent reduced by ALD; ADM22-52 and CGRP8-37 can both inhibit the effect of IMD1-53 on ALD, it suggests that ADM22-52 and CGRP8-37 can antagonize IMD1-53 receptor;ALD can activate ERK signal transduction path. IMD1-53can inhibit p-ERK expression reduced by ALD, it suggests that IMD1-53 can inhibit CFs proliferation by ERK signal transduction path with the result of improving myocardial fibrosis.
引文
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