降钙素基因相关肽抑制异丙肾上腺素诱导心肌重构的作用及机制研究
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摘要
研究背景
心肌重构是指心肌在多种病理情况下(如缺血、压力超负荷等)作出的适应性反应,包括心肌细胞肥大、间质纤维化和心肌细胞凋亡等。早期的重构在短期内对维持心功能具有一定的积极作用,但持续的重构会导致心功能失代偿而出现心力衰竭。最近的研究表明,辣椒素敏感的感觉神经功能低下以及microRNA-1、microRNA-133a和结缔组织生长因子(CTGF)的表达异常可能参与了心肌重构的形成。敲除辣椒素受体(VR1)可加重心肌缺血诱导的心肌重构,激活VR1促进感觉神经递质的释放则具有改善心功能的作用,说明病理状态下的心肌重构可能与感觉神经功能低下有关。吴茱萸次碱(Rut)是从中药吴茱萸中提取的一种生物碱,可通过激活VR1促进感觉神经递质——降钙素基因相关肽(CGRP)的合成和释放发挥一系列的心血管保护作用。基于心肌重构可能与感觉神经功能低下有关,因此本实验以异丙肾上腺素(Iso)诱导的心肌重构为模型,探讨降钙素基因相关肽(CGRP)在心肌重构中的作用和机制；并探讨吴茱萸次碱(Rut)对心肌重构的作用和机制。
研究方法
动物实验
SD大鼠每天皮下给予Iso (5mg/kg,连续10天)诱导心肌重构模型,Rut治疗组在皮下注射Iso的同时,灌胃给予不同剂量的Rut(10mg/kg或40mg/kg)。给药结束后,检测大鼠心脏结构的变化(超声心动图)；分离心脏,测量全心重与体重以及左心室重与体重的比值；观察心肌细胞大小的改变(苏木素-伊红染色)以及肥大标志物心钠素(ANP)和脑钠素(BNP) mRNA表达(RT-PCR)的变化；检测心肌细胞凋亡指数(TUNEL染色)以及凋亡相关基因Bax和Bcl-2mRNA的表达(RT-PCR);观察心肌胶原沉积(Masson染色)以及Ⅰ、Ⅲ型胶原和结缔组织生长因子(CTGF) mRNA表达(RT-PCR)的变化；检测心肌组织microRNA-1和microRNA-133a的表达(real-time PCR);取血浆和背根神经节分别检测CGRP的血浆浓度(放射免疫法)和α、β-CGRP mRNA的表达(RT-PCR)。
细胞实验
体外培养的心肌细胞和心肌成纤维细胞,以Iso来诱导心肌细胞的凋亡和成纤维细胞的增殖,CGRP在Iso处理前1 h给予。药物处理结束后,观察细胞活力的变化(MTT)以及心肌细胞凋亡的改变(Hoechest染色和流式细胞术)；检测心肌细胞Bax和Bcl-2以及成纤维细胞Ⅰ、Ⅲ型胶原和结缔组织生长因子(CTGF) mRNA的表达(RT-PCR);观察心肌细胞microRNA-1和microRNA-133a表达的变化(real-time PCR)以及细胞内活性氧(ROS)水平的改变(DCFH-DA荧光法)。
研究结果
动物实验
与对照组相比,给予Iso后可明显增加大鼠的收缩末左室内径(LEVDs)、收缩末左室后壁厚度(LVPWTs)和舒张末左室后壁厚度(LVPWTd)以及全心重与体重、左心室重与体重的比值,同时心肌细胞横截面积和ANP、BNPmRNA的表达也显著增加；心肌细胞凋亡指数和Bax mRNA的表达较对照组明显升高,而Bcl-2的mRNA表达则显著降低；给予Iso后大鼠心肌组织中胶原的沉积以及Ⅰ、Ⅲ型胶原和CTGF mRNA的表达显著增加；Iso还可明显上调microRNA-1的表达,而microRNA-133a的表达则显著下调；Iso处理大鼠后可显著降低背根神经节α、β-CGRP mRNA的表达和血浆中CGRP的浓度。给予Rut可显著促进CGRP的合成和释放,同时心肌重构得到明显的改善,而预先应用CGRP耗竭剂——辣椒素耗竭CGRP后则可取消Rut的上述有益作用。
细胞实验
在心肌细胞,Iso处理后可显著降低细胞的活性,增加心肌细胞的凋亡；促凋亡基因BaxmRNA的表达在Iso处理后明显上调,而抗凋亡基因Bcl-2 mRNA的表达并无显著性改变,导致Bax与Bcl-2的比值明显增加；Iso可明显上调心肌细胞microRNA-1的表达以及下调microRNA-133a的表达；另外,Iso处理后还可显著升高细胞内ROS的水平；预先给予CGRP后,可明显降低ROS的产生以及抑制Iso诱导的microRNA-1和microRNA-133a表达的变化,同时心肌细胞的凋亡也显著降低,但CGRP的这种保护作用可被CGRP受体拮抗剂CGRP8-37所取消。
在心肌成纤维细胞,Iso处理后可明显增加细胞的增殖活性；Ⅰ、Ⅲ型胶原和结缔组织生长因子(CTGF) mRNA的表达也显著增加；细胞内ROS的水平在Iso处理后也明显高于对照组；预先应用CGRP后也可显著抑制Iso的上述效应,同样,CGRP的这种保护作用可被CGRP8-37所取消。
结论
1.辣椒素敏感感觉神经的功能减弱以及miRNA-1、miRNA-133a和CTGF的表达异常可能参与了Iso诱导的心肌重构的形成；
2.Rut可抑制Iso诱导的心肌重构,其机制与激活VR1促进CGRP的合成和释放,进而调节miRNA-1、miRNA-133a和CTGF的表达有关；
3. CGRP对miRNA-1、miRNA-133a和CTGF表达的调节可能与其抑制ROS的产生有关。
Cardiac remodeling is a pathological condition and ultimately progresses into heart failure. Although the initial remodeling seems to be adaptive and shows beneficial effects on maintaining the heart function in a short term, persistent remodeling may contribute to functional decompensation. Recently, it has been shown that the dysfunction of capsaicin-sensitive sensory nerves and the expression abnormality of microRNA-1, microRNA-133a and connective tissue growth factor (CTGF) may be involved in cardiac remodeling. Deletion of transient receptor potential vanilloid (TRPV1, also named capsaicin receptor, VR1) could exacerbate cardiac remodeling after myocardial infarction, however, stimulating the release of neurotransmitter of sensory nerves by activating VR1 could improve the cardiac function. These reports suggested that cardiac remodeling under pathological conditions might be related to the dysfunction of sensory nerve. Rutaecarpine (Rut) is a major quinazolinocarboline alkaloid isolated from Chinese herbal drug Wu-Chu-Yu, which exerts cardiovascular protective effects by stimulating the synthesis and release of calcitonin gene-related peptide (CGRP), the principal neurotransmitter of sensory nerves, by activation of VR1. Since the dysfunction of sensory nerve was involved in cardiac remodeling, the present study was designed to evaluate the role of CGRP in isoprenaline (Iso)-induced cardiac remodeling and the underlying mechanisms. The effects of Rut on cardiac remodeling and the underlying mechanisms were also explored.
METHODS
Animal experiments
Cardiac remodeling was induced by administration of isoprenaline (5 mg/kg, s.c.) for 10 days, different concentrations of rutaecarpine (10 or 40mg/kg, i.g.) were co-administrated with isoprenaline. At the end of the drugs treatment, the cardiac morphology changes were measured by echocardiogram; the hearts were harvested, and the heart weight (HW), left ventrucular weight (LVW) were recorded and normalized for body weight (BW); the morphology and the size of cardiac cells were evaluated by hematoxylin-eosin staining; the apoptosis of cardiomyocytes was analyzed by TUNEL staining; the collagen deposition was evaluated by Masson's trichrome staining; the plasma level of CGRP were measured by RIA assay; the expression of microRNA-1 and microRNA-133a was determined by real time PCR; the mRNA expression of atrial natriuretic peptide (ANP, a hypertrophy marker) and brain natriuretic peptide (BNP, a hypertrophy marker), Bax and Bcl-2, collagen typeⅠ,Ⅲand CTGF, and CGRP (αandβisoforms) were examined by RT-PCR.
Cell experiments
The cardiomyocytes and cardiac fibroblasts were pretreated with CGRP at different doses for 1 h before incubating with isoprenaline (Iso) for 48 h. At the end of the drugs treatment, the cell viability was measured by MTT; the rate of apoptotic cells was examined by hoechst staining and flow cytometry; the mRNA expression of Bax, Bcl-2, collagen typeⅠandⅢ, and connective tissue growth factor (CTGF) was detected by RT-PCR; the expression of microRNA-1 and microRNA-133a was measured by real time PCR; The intracellular reactive oxygen species (ROS) production was examined by DCFH-DA flurescent probe.
RESULTS
Animal experiments
In comparison with control group, isoprenaline (Iso) treatment significantly increased the left ventricular end-systolic diameter (LVEDs), left ventricular end-systolic posterior wall thickness (LVPWTs) and left ventricular end-diastolic posterior wall thickness (LVPWTd); the ratio of HW/BW and LVW/BW, caridac myocyte cross-sectional area (CSA) and hypertrophic gene expression were also dramatically increased. Administration of Iso significantly increased the percentage of TUNEL-positive cells and Bax mRNA expression, while the Bcl-2 mRNA expression was markedly decreased. Iso treatment could also remarkably increased myocardial collagen deposition and collagen typeⅠ,Ⅲand CTGF mRNA expression. In Iso-treated rats, the expression of microRNA-1 was significantly up-regulated, while the microRNA-133a was markedly down-regulated. In the this study, we also found that the CGRP mRNA expression in dorsal root ganglion and concentration in plasma were significantly decreased. Co-administration of rutaecarpine (Rut) with Iso could remarkably stimulate the synthesis and release of CGRP, and in turn attenuates the cardiac remodeling. However, the beneficial effect of Rut was inhibited by pretreatment of capsaicin, which selectively depletes endogenous CGRP.
Cell experiments
Isoprenaline (Iso) treatment significantly decreased the cell viabilty, increased the rate of apoptotic cells in H9c2 cardiomyocytes; the mRNA expression of Bax, a proapoptotic gene, was also remarkably up-regulated after Iso treatment; while the expression of Bcl-2, an antiapoptotic gene, was no significant change. Iso treatment could also increase the expression of microRNA-1, and decrease the expression of microRNA-133a. In addition, the intracellular reactive oxygen species (ROS) level was significantly increased in Iso-treated group. Pretreatment of calcitonin gene-related peptide (CGRP) could markedly decrease the generation of intracellular ROS, correct the abnormal expression of microRNA-1 and microRNA-133a induced by Iso, and in turn decreased the rate of apoptotic cells. However, the protective effect of CGRP was abolished by pretreatment of CGRP receptor antagonist CGRP8-37.
In cardiac fibroblasts, Iso treatment markedly increased the proliferation activity; the mRNA expression of collagen typeⅠandⅢand connective tissue growth factor (CTGF) was also significantly up-regulated; In addition, the intracellular reactive oxygen species (ROS) level was significantly increased in Iso-treated group. Pretreatment of CGRP could markedly inhibt these detrimental effects induced by Iso, the beneficial effect of CGRP was abolished by CGRP8-37.
CONCLUSIONS
1.The dysfunction of capsaicin-sensitive sensory nerves and the abnormal expression of microRNA-1, microRNA-133a and CTGF may be involved in Iso-induced cardiac remodeling.
2. Rut could inhibit Iso-induced cardiac remodeling, which was related to regulating the expression of microRNA-1, microRNA-133a and CTGF through stimulating the synthesis and release of CGRP.
3.The effect of CGRP on the expression of microRNA-1, microRNA-133a and CTGF may be associated with inhibiting the generation of intracellular ROS.
心肌重构是指心肌在多种病理情况下(如缺血、压力超负荷等)作出的适应性反应,包括心肌细胞肥大、间质纤维化和心肌细胞凋亡等。早期的重构在短期内对维持心功能具有一定的积极作用,但持续的重构会导致心功能失代偿而出现心力衰竭。最近的研究表明,辣椒素敏感的感觉神经功能低下以及microRNA-1、microRNA-133a和结缔组织生长因子(CTGF)的表达异常可能参与了心肌重构的形成。敲除辣椒素受体(VR1)可加重心肌缺血诱导的心肌重构,激活VR1促进感觉神经递质的释放则具有改善心功能的作用,说明病理状态下的心肌重构可能与感觉神经功能低下有关。吴茱萸次碱(Rut)是从中药吴茱萸中提取的一种生物碱,可通过激活VR1促进感觉神经递质——降钙素基因相关肽(CGRP)的合成和释放发挥一系列的心血管保护作用。基于心肌重构可能与感觉神经功能低下有关,因此本实验以异丙肾上腺素(Iso)诱导的心肌重构为模型,探讨降钙素基因相关肽(CGRP)在心肌重构中的作用和机制；并探讨吴茱萸次碱(Rut)对心肌重构的作用和机制。
研究方法
动物实验
SD大鼠每天皮下给予Iso (5mg/kg,连续10天)诱导心肌重构模型,Rut治疗组在皮下注射Iso的同时,灌胃给予不同剂量的Rut(10mg/kg或40mg/kg)。给药结束后,检测大鼠心脏结构的变化(超声心动图)；分离心脏,测量全心重与体重以及左心室重与体重的比值；观察心肌细胞大小的改变(苏木素-伊红染色)以及肥大标志物心钠素(ANP)和脑钠素(BNP) mRNA表达(RT-PCR)的变化；检测心肌细胞凋亡指数(TUNEL染色)以及凋亡相关基因Bax和Bcl-2mRNA的表达(RT-PCR);观察心肌胶原沉积(Masson染色)以及Ⅰ、Ⅲ型胶原和结缔组织生长因子(CTGF) mRNA表达(RT-PCR)的变化；检测心肌组织microRNA-1和microRNA-133a的表达(real-time PCR);取血浆和背根神经节分别检测CGRP的血浆浓度(放射免疫法)和α、β-CGRP mRNA的表达(RT-PCR)。
细胞实验
体外培养的心肌细胞和心肌成纤维细胞,以Iso来诱导心肌细胞的凋亡和成纤维细胞的增殖,CGRP在Iso处理前1 h给予。药物处理结束后,观察细胞活力的变化(MTT)以及心肌细胞凋亡的改变(Hoechest染色和流式细胞术)；检测心肌细胞Bax和Bcl-2以及成纤维细胞Ⅰ、Ⅲ型胶原和结缔组织生长因子(CTGF) mRNA的表达(RT-PCR);观察心肌细胞microRNA-1和microRNA-133a表达的变化(real-time PCR)以及细胞内活性氧(ROS)水平的改变(DCFH-DA荧光法)。
研究结果
动物实验
与对照组相比,给予Iso后可明显增加大鼠的收缩末左室内径(LEVDs)、收缩末左室后壁厚度(LVPWTs)和舒张末左室后壁厚度(LVPWTd)以及全心重与体重、左心室重与体重的比值,同时心肌细胞横截面积和ANP、BNPmRNA的表达也显著增加；心肌细胞凋亡指数和Bax mRNA的表达较对照组明显升高,而Bcl-2的mRNA表达则显著降低；给予Iso后大鼠心肌组织中胶原的沉积以及Ⅰ、Ⅲ型胶原和CTGF mRNA的表达显著增加；Iso还可明显上调microRNA-1的表达,而microRNA-133a的表达则显著下调；Iso处理大鼠后可显著降低背根神经节α、β-CGRP mRNA的表达和血浆中CGRP的浓度。给予Rut可显著促进CGRP的合成和释放,同时心肌重构得到明显的改善,而预先应用CGRP耗竭剂——辣椒素耗竭CGRP后则可取消Rut的上述有益作用。
细胞实验
在心肌细胞,Iso处理后可显著降低细胞的活性,增加心肌细胞的凋亡；促凋亡基因BaxmRNA的表达在Iso处理后明显上调,而抗凋亡基因Bcl-2 mRNA的表达并无显著性改变,导致Bax与Bcl-2的比值明显增加；Iso可明显上调心肌细胞microRNA-1的表达以及下调microRNA-133a的表达；另外,Iso处理后还可显著升高细胞内ROS的水平；预先给予CGRP后,可明显降低ROS的产生以及抑制Iso诱导的microRNA-1和microRNA-133a表达的变化,同时心肌细胞的凋亡也显著降低,但CGRP的这种保护作用可被CGRP受体拮抗剂CGRP8-37所取消。
在心肌成纤维细胞,Iso处理后可明显增加细胞的增殖活性；Ⅰ、Ⅲ型胶原和结缔组织生长因子(CTGF) mRNA的表达也显著增加；细胞内ROS的水平在Iso处理后也明显高于对照组；预先应用CGRP后也可显著抑制Iso的上述效应,同样,CGRP的这种保护作用可被CGRP8-37所取消。
结论
1.辣椒素敏感感觉神经的功能减弱以及miRNA-1、miRNA-133a和CTGF的表达异常可能参与了Iso诱导的心肌重构的形成；
2.Rut可抑制Iso诱导的心肌重构,其机制与激活VR1促进CGRP的合成和释放,进而调节miRNA-1、miRNA-133a和CTGF的表达有关；
3. CGRP对miRNA-1、miRNA-133a和CTGF表达的调节可能与其抑制ROS的产生有关。
Cardiac remodeling is a pathological condition and ultimately progresses into heart failure. Although the initial remodeling seems to be adaptive and shows beneficial effects on maintaining the heart function in a short term, persistent remodeling may contribute to functional decompensation. Recently, it has been shown that the dysfunction of capsaicin-sensitive sensory nerves and the expression abnormality of microRNA-1, microRNA-133a and connective tissue growth factor (CTGF) may be involved in cardiac remodeling. Deletion of transient receptor potential vanilloid (TRPV1, also named capsaicin receptor, VR1) could exacerbate cardiac remodeling after myocardial infarction, however, stimulating the release of neurotransmitter of sensory nerves by activating VR1 could improve the cardiac function. These reports suggested that cardiac remodeling under pathological conditions might be related to the dysfunction of sensory nerve. Rutaecarpine (Rut) is a major quinazolinocarboline alkaloid isolated from Chinese herbal drug Wu-Chu-Yu, which exerts cardiovascular protective effects by stimulating the synthesis and release of calcitonin gene-related peptide (CGRP), the principal neurotransmitter of sensory nerves, by activation of VR1. Since the dysfunction of sensory nerve was involved in cardiac remodeling, the present study was designed to evaluate the role of CGRP in isoprenaline (Iso)-induced cardiac remodeling and the underlying mechanisms. The effects of Rut on cardiac remodeling and the underlying mechanisms were also explored.
METHODS
Animal experiments
Cardiac remodeling was induced by administration of isoprenaline (5 mg/kg, s.c.) for 10 days, different concentrations of rutaecarpine (10 or 40mg/kg, i.g.) were co-administrated with isoprenaline. At the end of the drugs treatment, the cardiac morphology changes were measured by echocardiogram; the hearts were harvested, and the heart weight (HW), left ventrucular weight (LVW) were recorded and normalized for body weight (BW); the morphology and the size of cardiac cells were evaluated by hematoxylin-eosin staining; the apoptosis of cardiomyocytes was analyzed by TUNEL staining; the collagen deposition was evaluated by Masson's trichrome staining; the plasma level of CGRP were measured by RIA assay; the expression of microRNA-1 and microRNA-133a was determined by real time PCR; the mRNA expression of atrial natriuretic peptide (ANP, a hypertrophy marker) and brain natriuretic peptide (BNP, a hypertrophy marker), Bax and Bcl-2, collagen typeⅠ,Ⅲand CTGF, and CGRP (αandβisoforms) were examined by RT-PCR.
Cell experiments
The cardiomyocytes and cardiac fibroblasts were pretreated with CGRP at different doses for 1 h before incubating with isoprenaline (Iso) for 48 h. At the end of the drugs treatment, the cell viability was measured by MTT; the rate of apoptotic cells was examined by hoechst staining and flow cytometry; the mRNA expression of Bax, Bcl-2, collagen typeⅠandⅢ, and connective tissue growth factor (CTGF) was detected by RT-PCR; the expression of microRNA-1 and microRNA-133a was measured by real time PCR; The intracellular reactive oxygen species (ROS) production was examined by DCFH-DA flurescent probe.
RESULTS
Animal experiments
In comparison with control group, isoprenaline (Iso) treatment significantly increased the left ventricular end-systolic diameter (LVEDs), left ventricular end-systolic posterior wall thickness (LVPWTs) and left ventricular end-diastolic posterior wall thickness (LVPWTd); the ratio of HW/BW and LVW/BW, caridac myocyte cross-sectional area (CSA) and hypertrophic gene expression were also dramatically increased. Administration of Iso significantly increased the percentage of TUNEL-positive cells and Bax mRNA expression, while the Bcl-2 mRNA expression was markedly decreased. Iso treatment could also remarkably increased myocardial collagen deposition and collagen typeⅠ,Ⅲand CTGF mRNA expression. In Iso-treated rats, the expression of microRNA-1 was significantly up-regulated, while the microRNA-133a was markedly down-regulated. In the this study, we also found that the CGRP mRNA expression in dorsal root ganglion and concentration in plasma were significantly decreased. Co-administration of rutaecarpine (Rut) with Iso could remarkably stimulate the synthesis and release of CGRP, and in turn attenuates the cardiac remodeling. However, the beneficial effect of Rut was inhibited by pretreatment of capsaicin, which selectively depletes endogenous CGRP.
Cell experiments
Isoprenaline (Iso) treatment significantly decreased the cell viabilty, increased the rate of apoptotic cells in H9c2 cardiomyocytes; the mRNA expression of Bax, a proapoptotic gene, was also remarkably up-regulated after Iso treatment; while the expression of Bcl-2, an antiapoptotic gene, was no significant change. Iso treatment could also increase the expression of microRNA-1, and decrease the expression of microRNA-133a. In addition, the intracellular reactive oxygen species (ROS) level was significantly increased in Iso-treated group. Pretreatment of calcitonin gene-related peptide (CGRP) could markedly decrease the generation of intracellular ROS, correct the abnormal expression of microRNA-1 and microRNA-133a induced by Iso, and in turn decreased the rate of apoptotic cells. However, the protective effect of CGRP was abolished by pretreatment of CGRP receptor antagonist CGRP8-37.
In cardiac fibroblasts, Iso treatment markedly increased the proliferation activity; the mRNA expression of collagen typeⅠandⅢand connective tissue growth factor (CTGF) was also significantly up-regulated; In addition, the intracellular reactive oxygen species (ROS) level was significantly increased in Iso-treated group. Pretreatment of CGRP could markedly inhibt these detrimental effects induced by Iso, the beneficial effect of CGRP was abolished by CGRP8-37.
CONCLUSIONS
1.The dysfunction of capsaicin-sensitive sensory nerves and the abnormal expression of microRNA-1, microRNA-133a and CTGF may be involved in Iso-induced cardiac remodeling.
2. Rut could inhibit Iso-induced cardiac remodeling, which was related to regulating the expression of microRNA-1, microRNA-133a and CTGF through stimulating the synthesis and release of CGRP.
3.The effect of CGRP on the expression of microRNA-1, microRNA-133a and CTGF may be associated with inhibiting the generation of intracellular ROS.
引文
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