心脏局部血管紧张素Ⅱ在噪声暴露致心肌损伤中的作用和机制
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摘要
目的:交通噪声、建筑噪声、社会生活噪声,不但干扰正常的工作和休息,而且影响身体健康。WHO报告指出心血管疾病是目前死亡率最高的疾病。流行病学调查显示噪声影响心血管系统,造成血压升高、心电图异常,甚至增加缺血性心脏病的危险性,对健康产生极大危害。但该方面的实验室研究较少,其致病机制尚未明确。心脏局部肾素-血管紧张素系统(renin-angiotensin system,RAS)与多种心脏疾病相关,如心肌梗塞、心脏肥大、心脏重塑、心衰等。当心脏局部RAS兴奋,其关键效应分子血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)水平升高,与其受体(AngⅡreceptor, AT)结合,促发下游信号转导过程,引起心肌收缩力增强,心肌蛋白质合成加速,心肌结构改变等。另外,AngⅡ可激活尼克酰胺腺嘌呤二核苷酸磷酸氧化酶(nicotinamide adeine dincleotide phosphate oxidase, NADPH氧化酶),该酶是心血管系统产生活性氧(reactive oxygen species, ROS)的主要酶体。并且研究发现ROS可能参与了噪声损伤机体的过程。那么心脏RAS是否在噪声暴露时,通过影响来源于NADPH氧化酶的ROS的产生,并启动下游信号转导分子,从而致心肌损伤的作用尚不清楚。因此本研究以心脏局部RAS为切入点,观察噪声暴露及给予AT1受体阻断剂(AngⅡtypeⅠreceptor blocker,ARB)-替米沙坦(Telmisartan)干预后心脏的变化,如心电图的改变、心脏氧化/抗氧化指标的变化;心脏RAS主要成分的变化;PKC介导的NADPH氧化酶/ROS信号通路的改变,来探讨局部RAS在噪声暴露致心肌损伤中的作用及其信号转导途径,为进一步认识噪声的心血管危害及预防措施研究提供理论和实验依据。
方法:健康成年雄性SD大鼠,耳廓反射灵敏,体质量140-150g,暴露于100dB白噪声,6h/d,连续12周。采用电镜观察心肌超微结构,采用生化法观察心肌组织MDA、T-AOC来反映心肌氧化损伤,放射免疫法检测循环、心肌AngⅡ水平的变化,荧光定量RT-PCR法检测心肌AT1A受体、血管紧张素原(angiotensinogen)mRNA表达水平变化,以探讨长期噪声暴露对心肌的损伤,及对心脏RAS的影响。在该模型的基础上,噪声暴露同时给予替米沙坦灌胃,采用电生理、形态学、生化学、ELISA、RT-PCR、Western blotting等技术方法,观察心肌形态结构、氧化/抗氧化能力、心脏RAS、NADPH氧化酶等指标的变化,以期明确通过阻断AT1受体,阻止AngⅡ作用的发挥,是否能减轻噪声对心肌的损伤,以及噪声暴露引起心肌氧化损伤是否与NADPH氧化酶相关,阐明噪声损伤心肌的机制。
结果:
1、100dB,6h/d,12wk,白噪声暴露可轻度损伤大鼠听力,表现为ABR阈值升高、波潜伏期延长。
2、长期噪声暴露可引起心电图改变,噪声暴露组心率(HR)(291.22 bpm)较正常组(379.63 bpm)明显降低(p<0.01);噪声暴露组心电图P波时间、P-R间期、QRS间期延长,P波电压增大;替米沙坦干预组HR(312.61 bpm)较噪声暴露组有升高趋势,但无统计学差异(p>0.05);替米沙坦干预组P波电压下降,较噪声暴露组明显降低(p<0.01)。
3、长期噪声暴露后,大鼠心肌超微结构损伤,表现为线粒体聚集、肿胀、嵴消失甚至呈空泡状;心肌纤维排列紊乱,甚至溶解消失。替米沙坦干预可部分减轻噪声对心肌超微结构的损伤,体现为线粒体、心肌纤维损伤程度减轻。
4、噪声暴露组心肌组织超氧阴离子(O2–)、MDA浓度较正常对照组明显升高(p<0.01,p<0.05),噪声暴露组SOD活性较正常对照组有降低趋势,差异不显著(p>0.05),噪声暴露组T-AOC较正常对照组明显降低(p<0.01)。替米沙坦干预组心肌组织O2–、MDA浓度较噪声暴露组明显降低(p<0.01),较正常对照组无明显差异(p>0.05);替米沙坦干预组心肌组织SOD活性较噪声暴露组明显升高(p<0.01),较正常对照组无明显差异(p>0.05);替米沙坦干预组心肌组织T-AOC较噪声暴露组有升高趋势,差异不显著(p>0.05),较正常对照组无明显差异(p>0.05)。说明噪声暴露可引起心肌组织ROS升高、脂质过氧化损伤,可降低心肌组织抗氧化能力,引起心肌氧化损伤;替米沙坦干预可以改善心肌氧化/抗氧化状态,增强心肌抗氧化能力、减轻氧化损伤。
5、长期噪声暴露可引起循环、心脏AngⅡ水平较正常对照组明显升高(p<0.05,p<0.01)。噪声暴露组心肌AGT mRNA表达较正常对照组有升高趋势,但无统计学意义(p>0.05)。噪声暴露组心肌AT1A mRNA表达较正常对照组明显增加(p<0.01)。替米沙坦干预组AngⅡ浓度和AGT mRNA表达水平较噪声暴露组、正常对照组明显降低(p<0.01);替米沙坦干预组AT1A mRNA表达水平较噪声暴露组明显降低(p<0.01),较正常对照组有降低趋势,但差异不显著(p>0.05)。说明噪声暴露可兴奋心脏RAS,替米沙坦干预可抑制心脏RAS,降低心肌AngⅡ水平、抑制AGT、AT1A mRNA表达。
6、噪声暴露组、替米沙坦干预组心肌蛋白激酶C(PKC)mRNA表达较正常对照组明显增加(p<0.01);替米沙坦干预组PKC mRNA表达较噪声暴露组有降低趋势,但无统计学差异(p>0.05)。噪声暴露组NADPH氧化酶亚基p47phox、gp91phox、p22phox mRNA表达较正常对照组明显增加(p<0.05),p47phox蛋白表达较正常对照组明显增加(p<0.01)。替米沙坦干预组NADPH氧化酶亚基p47phox mRNA和蛋白表达较噪声暴露组有降低趋势,但无统计学意义(p>0.05);替米沙坦干预组NADPH氧化酶亚基gp91phox、p22phox mRNA表达较噪声暴露组明显降低(p<0.05)。
结论:
1、长期噪声暴露后,大鼠心电图出现异常;大鼠心肌线粒体损伤严重,心肌纤维排列紊乱,甚至溶解消失。说明长期接触噪声不仅影响心脏功能,还影响心肌形态结构。
2、噪声暴露可引起心肌氧化/抗氧化失衡,导致氧化损伤;给予替米沙坦干预可以提高心肌抗氧化能力,减轻氧化损伤,说明ROS增多是噪声损伤心肌的机理之一,且通过AT1受体介导。
3、噪声暴露可引起心脏AngⅡ水平升高,AGT、AT1A mRNA基因表达增多;给予替米沙坦可以抑制心脏RAS,降低AngⅡ水平,抑制AGT、AT1A mRNA基因表达,说明噪声暴露可以兴奋心脏RAS,给予替米沙坦干预可以抑制心脏RAS过度兴奋。
4、噪声暴露可使心肌PKC表达增多,NADPH氧化酶表达增多;给予替米沙坦可以一定程度抑制PKC、NADPH氧化酶亚基表达,说明PKC/NADPH氧化酶途径可能介导AngⅡ损伤心肌过程。
综上,噪声损伤心肌可能机制为:噪声暴露引发心脏RAS兴奋,高水平的AngⅡ与其受体结合,激活PKC,促使P47phox激活,从而促进了NADPH氧化酶的组装,组装好的NADPH氧化酶具有了催化活性,通过催化电子传递过程产生ROS,最终导致心肌氧化损伤。这些研究结果为进一步阐明噪声导致心肌损伤的机制提供了启示,并为研究噪声导致心肌损伤的防护措施提供新的实验依据及思路。
OBJECTIVE: Noise pollution has become an increasingly serious problem. Traffic noise、construction noise、community noise have not only disturbed people's normal life, but also affected their health. The World Health Organization has reported cardiovascular disease as the highest cause of mortality. Epidemiological studies suggested that noise affects the cardiovascular system. Noise can increase the blood pressure and electrocardiogram abnormality rate, enve increase the relative risk of ischemic heart disease, which may affect people’s health seriously. However, few laboratory-based studied have been done in this area. The exact mechanism of noise-induced cardiovascular disease has not been fully explored. Local cardiac renin-angiotensin system (RAS) is related to a variety of cardiovascular diseases such as myocardial infarction, cardiac hypertrophy, cardiac remolding and heart failure. Studies have suggested that when the local RAS is stimulated, angiotensin II (Ang II) is increased, binds with Ang II receptor (AT), and therefore triggers signal transduction. This causes the enhancement of cardiomyocytes contractility, acceleration of protein synthesis and the rearrangement of cardiomyocytes, eventually leading to cardiomyocyte apoptosis, necrosis, hypertrophy, and remodeling. Research has demonstrated that Ang II can stimulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the primary enzyme to produce reactive oxygen species (ROS) in the cardiovascular system. Studies have also shown that noise exposure can produce ROS in the blood and cochlea. It has not yet been determined whether cardiac RAS mediated any of the effects of noise on heart, or whether ROS derived by RAS mediated the effects of noise on heart. Against this background, we plan to investigate the alteration of cardiac RAS, electrocardiogram, the index of oxidation/antioxidation, the NADPH oxidase subunits and PKC in rat hearts damaged by noise treated with Telmisartan. Based on these changes, this research aims to explore the role of the cardiac RAS in myocardial injury caused by noise exposure and its path of signal transduction, and therefore provide more theoretical and experimental basis for understanding the influence of noise exposure on the cardiovascular system and eventual implications for prevention.
METHODS: First, healthy male rats, weighted 140-150g, were exposed to 100dB white niose, 6h/d, 12 wk, building the animal model of heart damaged by noise, according to cardiomyocytes ultrastructure and the oxidative indicies of MDA content and T-AOC in myocardium. And then, radio-immunity method was used to detect the content of Ang II in plasm and myocardium; fluorescent quantitation method of RT-PCR was used to detect the expression of AGT and AT1A mRNA in myocardium. Second, on the basis of this model, ARB was administrated before noise exposure to observe the role of the Ang II, the indicies including myocardiac ultrastructure,electrocardiogram,oxidant/antioxidant, cardiac RAS, expression of NADPH oxidase and PKC. ARB was applied to block the action of Ang II, to explore whether it can reduce noise-induced myocardium impairment and whether oxidative damage caused by noise would be relate to NADPH oxidase, through which to clarify the underlying mechanisms of noise-induced myocardium damaged.
RESULTS:
1. The hearing of rat was damaged by long term noise exposure with white noise of 100dB, 6h/d, 12 wk, showing the thresholds of ABR increased and peak latency extended.
2. Electrocardiogram was changed by long term noise exposure. The HR of noise -exposure group(291.22 bpm) was significantly decreased(p<0.01), comparing with that of the normal control group(379.63 bpm). The duration of P wave, the interval of P-R, and the interval of QRS were extended of the noise-exposure group. The voltage of P wave was raised of the noise-exposure group. The HR of Telmisartan intervention group(291.22 bpm) had the tendency of accelation, but had no significance(p>0.05), comparing with the noise-exposure group. The voltage of P wave was decreased significantly comparing with that of the noise-exposure group.
3. Long term noise exposure damaged the myocardium, showing mitochondrial accumulating, swelling, cristae disappearing, even vacuoles happen. The damage of mitochondrial and myocardium were relieved by Telmisartan intervention.
4. The O2–and MDA content of myocardium of noise-exposure group were significantly raised(p<0.01, p<0.05), comaring with the normal control group. The SOD activity of noise-exposure group was unsignificantly changed(p>0.05), comparing with the normal control group. The T-AOC of noise-exposure group was significantly decreased(p<0.01), comparing with that of the normal control group. Telmisartan intervention may raise the SOD activity and T-AOC in the myocardium, decrease the O2–and MDA content of myocardium after noise exposure, Which indicating noise exposure can increase ROS generating, damaged antioxidant capability of myocardium, and then lead to myocardium oxidative damaged. Telmisartan can raise the antioxidant capability of myocardium, reduce the oxidative damaged.
5. Long term noise exposure can raise the AngⅡcontent of plasma and myocardium(p<0.05,p<0.01), comparing with the normal control group. The expression of AGT mRNA of noise-exposure group had the tendency of augmentation, comparing with the normal control group. The expression of AT1A mRNA of noise-exposure group was significantly raised(p<0.01), comparing with the normal control group. The AngⅡcontent , the expression of AGT and AT1A mRNA of myocardium of the telmisartan intervention group were decreased significantly(p<0.01), comaring with the noise-exposure group. 6. Noise can cause increased expression of PKC and NADPH oxidase subunits: p47phox, p22phox, gp91phox. Telmisartan was shown to inhibit the expression of PKC and NADPH oxidase subunits.
CONCLUSION:
1. Heart damaged by noise may be related to oxidative stress injury.
2. Noise exposure can stimulate local cardiac RAS.
3. Heart damaged by noise may be related to overexpression of PKC and NADPH oxidase.
4. Heart damaged by noise may be mediated by Ang II-AT1 pathway.
5 Telmisartan can reduce heart injury by blocking the action of Ang II. One of the signal transduction process of noise-induced heart damaged is composed of the following steps: noise exposure induction of overexcitation of cardiac RAS, which increas Ang II levels, binds with AT1A, activates of PKC, increases of P47 expression, and augments NADPH oxidase assembly. Assembled NADPH oxidase has enzyme activity, which then catalyzes electron transport to produce ROS. ROS should be the signal messenger, activating signal pathways, and causing heart injury.
方法:健康成年雄性SD大鼠,耳廓反射灵敏,体质量140-150g,暴露于100dB白噪声,6h/d,连续12周。采用电镜观察心肌超微结构,采用生化法观察心肌组织MDA、T-AOC来反映心肌氧化损伤,放射免疫法检测循环、心肌AngⅡ水平的变化,荧光定量RT-PCR法检测心肌AT1A受体、血管紧张素原(angiotensinogen)mRNA表达水平变化,以探讨长期噪声暴露对心肌的损伤,及对心脏RAS的影响。在该模型的基础上,噪声暴露同时给予替米沙坦灌胃,采用电生理、形态学、生化学、ELISA、RT-PCR、Western blotting等技术方法,观察心肌形态结构、氧化/抗氧化能力、心脏RAS、NADPH氧化酶等指标的变化,以期明确通过阻断AT1受体,阻止AngⅡ作用的发挥,是否能减轻噪声对心肌的损伤,以及噪声暴露引起心肌氧化损伤是否与NADPH氧化酶相关,阐明噪声损伤心肌的机制。
结果:
1、100dB,6h/d,12wk,白噪声暴露可轻度损伤大鼠听力,表现为ABR阈值升高、波潜伏期延长。
2、长期噪声暴露可引起心电图改变,噪声暴露组心率(HR)(291.22 bpm)较正常组(379.63 bpm)明显降低(p<0.01);噪声暴露组心电图P波时间、P-R间期、QRS间期延长,P波电压增大;替米沙坦干预组HR(312.61 bpm)较噪声暴露组有升高趋势,但无统计学差异(p>0.05);替米沙坦干预组P波电压下降,较噪声暴露组明显降低(p<0.01)。
3、长期噪声暴露后,大鼠心肌超微结构损伤,表现为线粒体聚集、肿胀、嵴消失甚至呈空泡状;心肌纤维排列紊乱,甚至溶解消失。替米沙坦干预可部分减轻噪声对心肌超微结构的损伤,体现为线粒体、心肌纤维损伤程度减轻。
4、噪声暴露组心肌组织超氧阴离子(O2–)、MDA浓度较正常对照组明显升高(p<0.01,p<0.05),噪声暴露组SOD活性较正常对照组有降低趋势,差异不显著(p>0.05),噪声暴露组T-AOC较正常对照组明显降低(p<0.01)。替米沙坦干预组心肌组织O2–、MDA浓度较噪声暴露组明显降低(p<0.01),较正常对照组无明显差异(p>0.05);替米沙坦干预组心肌组织SOD活性较噪声暴露组明显升高(p<0.01),较正常对照组无明显差异(p>0.05);替米沙坦干预组心肌组织T-AOC较噪声暴露组有升高趋势,差异不显著(p>0.05),较正常对照组无明显差异(p>0.05)。说明噪声暴露可引起心肌组织ROS升高、脂质过氧化损伤,可降低心肌组织抗氧化能力,引起心肌氧化损伤;替米沙坦干预可以改善心肌氧化/抗氧化状态,增强心肌抗氧化能力、减轻氧化损伤。
5、长期噪声暴露可引起循环、心脏AngⅡ水平较正常对照组明显升高(p<0.05,p<0.01)。噪声暴露组心肌AGT mRNA表达较正常对照组有升高趋势,但无统计学意义(p>0.05)。噪声暴露组心肌AT1A mRNA表达较正常对照组明显增加(p<0.01)。替米沙坦干预组AngⅡ浓度和AGT mRNA表达水平较噪声暴露组、正常对照组明显降低(p<0.01);替米沙坦干预组AT1A mRNA表达水平较噪声暴露组明显降低(p<0.01),较正常对照组有降低趋势,但差异不显著(p>0.05)。说明噪声暴露可兴奋心脏RAS,替米沙坦干预可抑制心脏RAS,降低心肌AngⅡ水平、抑制AGT、AT1A mRNA表达。
6、噪声暴露组、替米沙坦干预组心肌蛋白激酶C(PKC)mRNA表达较正常对照组明显增加(p<0.01);替米沙坦干预组PKC mRNA表达较噪声暴露组有降低趋势,但无统计学差异(p>0.05)。噪声暴露组NADPH氧化酶亚基p47phox、gp91phox、p22phox mRNA表达较正常对照组明显增加(p<0.05),p47phox蛋白表达较正常对照组明显增加(p<0.01)。替米沙坦干预组NADPH氧化酶亚基p47phox mRNA和蛋白表达较噪声暴露组有降低趋势,但无统计学意义(p>0.05);替米沙坦干预组NADPH氧化酶亚基gp91phox、p22phox mRNA表达较噪声暴露组明显降低(p<0.05)。
结论:
1、长期噪声暴露后,大鼠心电图出现异常;大鼠心肌线粒体损伤严重,心肌纤维排列紊乱,甚至溶解消失。说明长期接触噪声不仅影响心脏功能,还影响心肌形态结构。
2、噪声暴露可引起心肌氧化/抗氧化失衡,导致氧化损伤;给予替米沙坦干预可以提高心肌抗氧化能力,减轻氧化损伤,说明ROS增多是噪声损伤心肌的机理之一,且通过AT1受体介导。
3、噪声暴露可引起心脏AngⅡ水平升高,AGT、AT1A mRNA基因表达增多;给予替米沙坦可以抑制心脏RAS,降低AngⅡ水平,抑制AGT、AT1A mRNA基因表达,说明噪声暴露可以兴奋心脏RAS,给予替米沙坦干预可以抑制心脏RAS过度兴奋。
4、噪声暴露可使心肌PKC表达增多,NADPH氧化酶表达增多;给予替米沙坦可以一定程度抑制PKC、NADPH氧化酶亚基表达,说明PKC/NADPH氧化酶途径可能介导AngⅡ损伤心肌过程。
综上,噪声损伤心肌可能机制为:噪声暴露引发心脏RAS兴奋,高水平的AngⅡ与其受体结合,激活PKC,促使P47phox激活,从而促进了NADPH氧化酶的组装,组装好的NADPH氧化酶具有了催化活性,通过催化电子传递过程产生ROS,最终导致心肌氧化损伤。这些研究结果为进一步阐明噪声导致心肌损伤的机制提供了启示,并为研究噪声导致心肌损伤的防护措施提供新的实验依据及思路。
OBJECTIVE: Noise pollution has become an increasingly serious problem. Traffic noise、construction noise、community noise have not only disturbed people's normal life, but also affected their health. The World Health Organization has reported cardiovascular disease as the highest cause of mortality. Epidemiological studies suggested that noise affects the cardiovascular system. Noise can increase the blood pressure and electrocardiogram abnormality rate, enve increase the relative risk of ischemic heart disease, which may affect people’s health seriously. However, few laboratory-based studied have been done in this area. The exact mechanism of noise-induced cardiovascular disease has not been fully explored. Local cardiac renin-angiotensin system (RAS) is related to a variety of cardiovascular diseases such as myocardial infarction, cardiac hypertrophy, cardiac remolding and heart failure. Studies have suggested that when the local RAS is stimulated, angiotensin II (Ang II) is increased, binds with Ang II receptor (AT), and therefore triggers signal transduction. This causes the enhancement of cardiomyocytes contractility, acceleration of protein synthesis and the rearrangement of cardiomyocytes, eventually leading to cardiomyocyte apoptosis, necrosis, hypertrophy, and remodeling. Research has demonstrated that Ang II can stimulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the primary enzyme to produce reactive oxygen species (ROS) in the cardiovascular system. Studies have also shown that noise exposure can produce ROS in the blood and cochlea. It has not yet been determined whether cardiac RAS mediated any of the effects of noise on heart, or whether ROS derived by RAS mediated the effects of noise on heart. Against this background, we plan to investigate the alteration of cardiac RAS, electrocardiogram, the index of oxidation/antioxidation, the NADPH oxidase subunits and PKC in rat hearts damaged by noise treated with Telmisartan. Based on these changes, this research aims to explore the role of the cardiac RAS in myocardial injury caused by noise exposure and its path of signal transduction, and therefore provide more theoretical and experimental basis for understanding the influence of noise exposure on the cardiovascular system and eventual implications for prevention.
METHODS: First, healthy male rats, weighted 140-150g, were exposed to 100dB white niose, 6h/d, 12 wk, building the animal model of heart damaged by noise, according to cardiomyocytes ultrastructure and the oxidative indicies of MDA content and T-AOC in myocardium. And then, radio-immunity method was used to detect the content of Ang II in plasm and myocardium; fluorescent quantitation method of RT-PCR was used to detect the expression of AGT and AT1A mRNA in myocardium. Second, on the basis of this model, ARB was administrated before noise exposure to observe the role of the Ang II, the indicies including myocardiac ultrastructure,electrocardiogram,oxidant/antioxidant, cardiac RAS, expression of NADPH oxidase and PKC. ARB was applied to block the action of Ang II, to explore whether it can reduce noise-induced myocardium impairment and whether oxidative damage caused by noise would be relate to NADPH oxidase, through which to clarify the underlying mechanisms of noise-induced myocardium damaged.
RESULTS:
1. The hearing of rat was damaged by long term noise exposure with white noise of 100dB, 6h/d, 12 wk, showing the thresholds of ABR increased and peak latency extended.
2. Electrocardiogram was changed by long term noise exposure. The HR of noise -exposure group(291.22 bpm) was significantly decreased(p<0.01), comparing with that of the normal control group(379.63 bpm). The duration of P wave, the interval of P-R, and the interval of QRS were extended of the noise-exposure group. The voltage of P wave was raised of the noise-exposure group. The HR of Telmisartan intervention group(291.22 bpm) had the tendency of accelation, but had no significance(p>0.05), comparing with the noise-exposure group. The voltage of P wave was decreased significantly comparing with that of the noise-exposure group.
3. Long term noise exposure damaged the myocardium, showing mitochondrial accumulating, swelling, cristae disappearing, even vacuoles happen. The damage of mitochondrial and myocardium were relieved by Telmisartan intervention.
4. The O2–and MDA content of myocardium of noise-exposure group were significantly raised(p<0.01, p<0.05), comaring with the normal control group. The SOD activity of noise-exposure group was unsignificantly changed(p>0.05), comparing with the normal control group. The T-AOC of noise-exposure group was significantly decreased(p<0.01), comparing with that of the normal control group. Telmisartan intervention may raise the SOD activity and T-AOC in the myocardium, decrease the O2–and MDA content of myocardium after noise exposure, Which indicating noise exposure can increase ROS generating, damaged antioxidant capability of myocardium, and then lead to myocardium oxidative damaged. Telmisartan can raise the antioxidant capability of myocardium, reduce the oxidative damaged.
5. Long term noise exposure can raise the AngⅡcontent of plasma and myocardium(p<0.05,p<0.01), comparing with the normal control group. The expression of AGT mRNA of noise-exposure group had the tendency of augmentation, comparing with the normal control group. The expression of AT1A mRNA of noise-exposure group was significantly raised(p<0.01), comparing with the normal control group. The AngⅡcontent , the expression of AGT and AT1A mRNA of myocardium of the telmisartan intervention group were decreased significantly(p<0.01), comaring with the noise-exposure group. 6. Noise can cause increased expression of PKC and NADPH oxidase subunits: p47phox, p22phox, gp91phox. Telmisartan was shown to inhibit the expression of PKC and NADPH oxidase subunits.
CONCLUSION:
1. Heart damaged by noise may be related to oxidative stress injury.
2. Noise exposure can stimulate local cardiac RAS.
3. Heart damaged by noise may be related to overexpression of PKC and NADPH oxidase.
4. Heart damaged by noise may be mediated by Ang II-AT1 pathway.
5 Telmisartan can reduce heart injury by blocking the action of Ang II. One of the signal transduction process of noise-induced heart damaged is composed of the following steps: noise exposure induction of overexcitation of cardiac RAS, which increas Ang II levels, binds with AT1A, activates of PKC, increases of P47 expression, and augments NADPH oxidase assembly. Assembled NADPH oxidase has enzyme activity, which then catalyzes electron transport to produce ROS. ROS should be the signal messenger, activating signal pathways, and causing heart injury.
引文
[1]、李会娟,曾琳,吕旌乔,等。北京市四环路临街某高层住宅环境噪声评价。环境与职业医学,2008,25(1):16-19。
[2]、高婷,吴锡南。某钢铁公司轧钢工人噪声暴露与听力损失的调查[J].中国药物与临床, 2010,l0(9):1017-1019.
[3]、尹嘉才,胡正元,周笃强,等.全军武器装备噪声的现状与分析[M].全军噪声协作组,1992:1-3.
[4]、Skinner C, Grimwood C. The National Noise Incidence Study 2000/2001 (United Kingdom): Vol 1 - Noise levels. BRE report 206344f, 2002.
[5]、Berglund B, Lindvall T, Schwela D, et al. Guidelines for community noise. 2000:20-34.
[6]、世界卫生组织,心血管疾病。实况报道,第317号(2011年1月)。http://www.who.int/mediacentre/factsheets/fs317/zh/index.html.
[7]、Gerber SE, Mulac A, Lamb ME. The cardiovascular response to acoustic stimuli. Audiology, 1977 Jan-Feb;16(1):1-10.
[8]、Idzior-Walu? B. Coronary risk factors in men occupationally exposed to vibration and noise. Eur Heart , 1987 Oct;8(10):1040-1046.
[9]、Babisch W, Gallacher JE, Elwood PC, et al. Traffic noise and cardiovascular risk. The Caerphilly study, first phase. Outdoor noise levels and risk factors. Arch Environ Health, 1988 Nov-Dec;43(6):407-414.
[10]、Ising H, Rebentisch E, Poustka F, et al. Annoyance and health risk caused by military low-altitude flight noise. Int Arch Occup Environ Health, 1990;62(5):357-363.
[11]、Haralabidis AS, Dimakopoulou K, Vigna-Taglianti F, et al. Acute effects of night-time noise exposure on blood pressure in populations living near airports. Eur Heart J, 2008 Mar;29(5):658-664.
[12]、Jarup L, Babisch W, Houthuijs D, et al. Hypertension and exposure to noise near airports: The HYENA study. Environ Health Perspect, 2008;116(3):329-333.
[13]、Kempen EE,Kruize H,Boshuizen HC,et al.The association between noise exposure and blood pressure and ischemic heart disease: a meta-analysis. Environ Health Perspect, 2002;110(3): 307-317.
[14]、Babisch W, Elwood PC, Ising H, et al. Traffic noise as a risk factor for myocardial infarction. Schriftenr Ver Wasser Boden Lufthyg, 1993;88:135-166.
[15]、Ising H, Kruppa B. Health effects caused by noise : Evidence in the literature from the past 25 years. Noise Health 2004;6(22):5-13.
[16]、Abbate C, Giorgianni C, MunaòF, et al. Effects of noise on functional cardiovascular parameters: a follow-up study. G Ital Med Lav Ergon, 2002 ;24(1):43-48.
[17]、Aydin Y, Kaltenbach M. Noise perception, heart rate and blood pressure in relation to aircraft noise in the vicinity of the Frankfurt airport. Clin Res Cardiol, 2007; 96(6):347-358.
[18]、Babisch W.Transportation noise and cardiovascular risk: Updated review and synthesis of epidemiological studies indicate that the evidence has increased.Noise Health, 2006 Jan-Mar;8(30):1-29.
[19]、Gan WQ, Davies HW, Demers PA. Exposure to occupational noise and cardiovascular disease in the United States: the National Health and Nutrition Examination Survey 1999-2004. Occup Environ Med, 2011 Mar;68(3):183-90.
[20]、Peterson EA, Augenstein JS, Hazelton CL, et al. Some cardiovascular effects of noise. J Aud Res, 1984, 24(1): 35-62.
[21]、Gesi M, Fornai F, Lenzi P, et al. Ultrastructural localization of calcium deposits in rat myocardium after loud noise exposure. J Submicrosc Cytol Pathol. 2000 ;32(4):585-590.
[22]、Okada A, Ariizumi M,Okamoto G. Study on the mechanism of the appearance of noise effects. Eur J Appl Physiol Occup Physiol, 1985,53(4):364-367.
[23]、Turkkan JS,Hienz RD,Harris AH.Novel long-term cardiovascular effects of industrial noise. Physiol Behav, 1984, Jul,33(1):21-26.
[24]、Maschke C,Rupp T,Hecht K. The influence of stressors on biochemical reactions-a review of present scientific findings with noise. Int J Hyg Environ Health,2000,203(1): 45-53.
[25]、Windle RJ, Wood SA, Lightman SL,et al. The pulsatile characteristics of Hypothalamo-Pituitary-Adrenal activity in female lewis and fischer 344 Rats and its relationship to differential stress responses.Endocr, 1998,139(10): 4044-4052.
[26]、Boer SF,Slangen JL,Gugten JV. Adaptation of plasma catecholamine and corticosterone responses to short-term repeated noise stress in rats. Physiol Behav,1988;44(2):273-280.
[27]、Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J, 1984,108(1):188-193.
[28]、Ising H,Babisch W,Kruppa B. Noise-Induced Endocrine Effects and Cardiovascular Risk. Noise Health. 1999;1(4):37-48.
[29]、Ferrario CM. Role of Angiotensin II in Cardiovascular Disease-Therapeutic Implications of More Than a Century of Research . JRAAS, 2006,7(1):3-14.
[30]、Ibrahim MM. RAS inhibition in hypertension. J Hum Hypertens, 2006;20(2):101-8.
[31]、周正谋,孙阿成,赵云涛,等.强噪声短期暴露对大鼠类内洋地黄素和血管紧张素Ⅱ的影响.中华劳动卫生职业病杂志,1995,13(6): 341-342
[32]、张素珍,徐永,万瑜,等。应激大鼠血浆与肾上腺组织血管紧张素Ⅱ的水平及ANGmRNA在肾上腺组织中的表达。广东医学院学报,2002,20(2):87-88
[33]、Sim?es MR, Ribeiro Júnior RF, Vescovi MV, et al. Acute lead exposure increases arterial pressure:role of the rennin-angiotensin system. PLoS One, 2011 Apr 11;6(4):e18730-18736.
[34]、Dostal DE, Baker KM. The Cardiac Renin-Angiotensin System : Conceptual, or a Regulator of Cardiac Function? Circ Res, 1999;85:643-650.
[35]、Chan WP, Fung ML, Nobiling R, et al. Activation of local renin-angiotensin system by chronic hypoxia in rat pancreas. Molecular and Cellular Endocrinology, 2000; 160:107–114.
[36]、Thomasa MA, Fleissner G, Sto¨hr M, et al. Localization of components of the renin–angiotensin system in the suprachiasmatic nucleus of normotensive Sprague–Dawley rats Part A. Angiotensin I/II, a light and electron microscopic study. Brain Research, 2004;1008:212–223.
[37]、Leung PS, Fung ML, Tam MS. Renin–angiotensin system in the carotid body .The International Journal of Biochemistry & Cell Biology, 2003; 35: 847–854.
[38]、Dostal DE, Rothblum KN, Chernin MI, et al. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in the neonatal rat heart. Am Physiol, 1992: 263:C838-850.
[39]、Dostal DE, Baker KM. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res, 1999; 85:643–650.
[40]、Li L, Yi-Ming W, Li ZZ, et al. Local RAS and inflammatory factors are involved in cardiovascular hypertrophy in spontaneously hypertensive rats. Pharmacol Res. 2008 Sep-Oct;58(3-4):196-201.
[41]、Oliveira EM, Sasaki MS, Cerêncio M, et al. Local renin-angiotensin system regulates left ventricular hypertrophy induced by swimming training independent of circulating renin: a pharmacological study [J]. J Renin Angiotensin Aldosterone Syst. 2009 Mar;10(1):15-23.
[42]、Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol ,2007;292:C82–97.
[43]、Whaley-Connell AT, Chowdhury NA, Hayden MR, et al. Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat. Am J Physiol Renal Physiol, 2006; 291:F1308-F1314.
[44]、Zou XJ, Yang L, Yao SL. Propofol depresses angiotensin II-inducedcardiomyocyte hypertrophy in vitro. Exp Biol Med (Maywood), 2008; 233(2): 200-208.
[45]、Nakagam H, Takemoto M, Liao LK. NADPH oxidase-derived superoxide anion mediates angiotensinⅡ-induced cardiac hypertrophy. J Mell Cell Cardiol,2003; 35(7):851-859.
[46]、Griendling KK, Minieri CA, Ollerenshaw JD, et al. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res, 1994;74(6):1141–8.
[47]、Oudot A, Vergely C, Ecarnot-Laubriet A, et al. Angiotensin II activates NADPH oxidase in isolated rat hearts subjected to ischaemia–reperfusion. European Journal of Pharmacology, 2003; 462:145– 154.
[48]、Kawahara T, Quinn MT, Lambeth JD, et al. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evolutionary Biology, 2007; 7:109-129.
[49]、Selemidis s, Sobey CG, Wingler K, et al. NADPH oxidases in the vasculature: Molecular features, roles in disease and pharmacological inhibition. Pharmacology Therapeutics, 2008;120: 254-291.
[50]、Matutea JD, Ariasa AA, Dinauer, MC, et al. p40phox: The last NADPH oxidase subunit. Blood Cells Molecules Diseases, 2005; 35: 291-302.
[51]、Lavigne MC, Malech HL, Holland, SM, et al. Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells. Circulation, 2001;104: 79–84.
[52]、Touyz RM, Chen X, Tabet F, et al. Expression of a functionally active gp91phox-containing neutrophiltype NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res, 2002; 90:1205-1213.
[53]、Hassanain HH, Gregg D, Marcelo ML, et al. Hypertension caused by transgenic overexpression of Rac1. Antioxid Redox Signal, 2007; 9: 91-100.
[54]、Livak KJ,Schmittgen TD.Analysis of relative gene expression data using real- time quantitative PCR and the 2 -⊿⊿CT method[J].Methods,2001,25(4):402—408.
[55]、Sobotova L, Jurkovicova J, Stefanikova Z, et al. Community response to environmental noise and the impact on cardiovascular risk score. Sci Total Environ, 2010 Feb,408(6):1264-70.
[56]、Berglund B, Lindvall T, Schwela D, et al. Guidelines for Community Noise[M]. World Health Organisation 2000;28-29.
[57]、Gerber SE, Mulac A, Lamb ME. The cardiovascular response to acoustic stimuli. Audiology. 1977;16(1):1-10.
[58]、Andrén L, Hansson L, Bj?rkman M, et al. Hemodynamic and hormonal changes induced by noise. Acta Med Scand Suppl. 1979;625:13-18.
[59]、Andrén L, Lindstedt G, Bj?rkman M, et al. Effect of noise on blood pressure and 'stress' hormones. Clin Sci (Lond) 1982;62(2):137-141.
[60]、Babisch W,Fromme H,Beyer A,et al.Increased catecholamine levels in urine in subjects exposed to road traffic noise:the role of stress homones in noise research.Environ Int,2001,26(7-8):475-481.
[61]、Paparelli A, Pellegrini A, Lenzi P, et al. Ultrastructural changes in atrial tissue of young and aged rats submitted to acute noise stress. J Submicrosc Cytol Pathol 1995;27(1):137-42.
[62]、Ivanovich E, Antov G. Enzyme changes in the myocardium of experimental animals exposed to noise of various intensities. Probl Khig 1981;6:9-14.
[63]、Softowa E, Malewa E, Zlatewa M. Histomorphological changes in the myocardium of experimental animals in long-term exposure to intense industrial noise. Zentralbl Allg Pathol 1983;127(1-2):85-89.
[64]、Lenzi P, Frenzilli G, Gesi M, et al. DNA damage associated with ultrastructural alterations in rat myocardium after loud noise exposure. Environ Health Perspect. 2003;111(4):467-471.
[65]、Gesi M, Pellegrini A, Lenzi P, et al. Effects of newly-developed benzodiazepine ligands on noise-induced mitochondrial damage in the rat. Ann Anat. 2000;182(4):311-318.
[66]、Bao G, Metreveli N, Fletcher EC, et al. Acute and chronic blood pressure response to recurrent acoustic arousal in rats.Am J Hypertens. 1999 May;12(5):504-510.
[67]、Marciniak W, Rodriguez E, Olszowska K, et al. Echocardiographic evalution in 485 aeronautical workers exposed to different noise environments. Aviat Space Environ Med, 1999, 70(3 Pt 2): A46-53.
[68]、Soldani P, Pellegrini A, Gesi M, et al. SEM/TEM investigation of rat cardiac subcellular alterations induced by changing duration of noise stress. Anat Rec, 1997, 248(4): 521-532.
[69]、Borutaite V, Vrown GC. Mitochondria in apoptosis of ischemic heart. FEBS Lett ,2003 Apr,541(1-3):1-5.
[70]、Weiss JN, Korge P, Honda HM, et al. Role of the mitochondrial permeability transition in myocardial disease. Circ Res, 2003,93(4):292-301.
[71]、Yamashita D, Jiang HY, Schacht J, et al. Delayed production of free radicals following noise exposure. Brain Res ,2004, 1019 (1–2): 201–209.
[72]、Uran SL, Caceres LG, Guelman LR. Effects of loud noise on hippocampal and cerebellar-related behaviors. Role of oxidative state. Brain Research, 2010(1361):102-114.
[73]、Khullar M, Relan V, Sherawat BS.Antioxidant activities and oxidative stress by- products in human hypertension[J].Hypertension, 2004, 43(2):7-8.
[74]、Kim YH, Lim DS, Lee JH, et a1.Gene expression profiling of oxidative stress on atrial fibrillation in humans[J].Exp Mol Med, 2003, 35(5): 336-349.
[75]、Saha S, Gandhi A, Das S, et al. Effect of noise stress on some cardiovascular parameters and audiovisual reaction time. Indian J Physiol Pharmacol, 1996, 40(1): 35-40.
[76]、Regecova V, Kellerova E. Effects of urban noise pollution on blood pressure and heart rate in preschool children. J Hypertens, 1995, 13(4) : 405-412.
[77]、唱斗,梁武,王生.高频稳态噪声对心血管系统影响的调查.中国职业医学, 2003, 30(2):25-27.
[78]、Dzau VJ, Ellison KE, Brody T, et al. A comparative study of the distributions of renin and angiotensinogen messenger ribonucleic acids in rat and mouse tissues. Endocrinology1987;120:2334–2338.
[79]、Dostal DE, Rothblum KC, Chernin MI, et al. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in neonatal rat heart. Am J Physiol. 1992;263:C838–C863.
[80]、Dostal DE, Rothblum KC, Baker KM. An improved method for absolute quantification of mRNA using multiplex polymerase chain reaction: determination of renin and angiotensinogen mRNA levels in various tissues. Anal Biochem. 1994;223:239–250.
[81]、Tsai CT, Lai LP, Hwang JJ,et al.Renin-angiotensin system component expression in the HL-1 atrial cell line and in a pig model of atrial fibrillation [J]. J Hypertens,2008;26(3):570-82.
[82]、Arakawa K, Urata H. Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension,2000; 36(): 638–641.
[83]、Urata H, Nishimura H, Ganten D. Chymase-dependent angiotensin II forming systems in humans. Am J Hypertens,1996. 9: 277–284,
[84]、Von Lutterotti N, Catanzaro DF, Sealey JE, et al. Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence. Circulation1994; 89: 493–498.
[85]、Kobori H, Ichihara A, Suzuki H, et al. Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism. Am J Physiol. 1997;273:H593–H599.
[86]、Mazzolai L, Nussberger J, Jean-Francois A, et al. Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension. 1998; 31:1324–1330.
[87]、Amaral SL, Papanek PE, Greene AS. Angiotensin II and VEGF are involved in angiogenesis induced by short-term exercise training. Am J Physiol Heart Circ Physiol, 2001, 281(3): H1163–H1169.
[88]、Chung IM, Kim YM, Yoo MH, et al. Immobilization stress induces endothelial dysfunction by oxidative stress via the activation of the angiotensin II/its type I receptor pathway. Atherosclerosis, 2010, 213(1): 109–114.
[89]、Wright JW, Dengerink HA, Miller JM, et al. Potential role of angiotensin II in noise-induced increases in inner ear blood flow. Hear Res, 1985,17(1):41-6.
[90]、Nakagami H , Takemoto M , Liao JK, et al. NADPH oxidase-derived superoxide anion mediates angiotensin II-induced cardiac hypertrophy.J Mol Cell Cardiol, 2003 July, 35(7): 851–859.
[91]、Lavigne MC, Malech HL, Holland SM, et al. Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells. Circulation,2001, 104: 79–84.
[92]、Heymes C, Bendall JK, Ratajczak P, et al. Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol, 2003, 41:2164– 2171.
[93]、Samuel CD, Nyssa EH, Louise AM, et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage:role of the NADPH and xanthine oxidases.Circulation,2005,112:1266-1273.
[94]、Mol1nau H, Wendt M,Szocs K, et al. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling .Circ Res, 2002,90(4):E58一E65
[95]、Ungvari Z, Csiszar A, Huang A, et al. A high pressure induces superoxide production in isolated arteries via protein kinase C一dependent activation of NAD(P) H oxidase.Circulation, 2003 ,108 (10) ;1253一1258
[96]、Qin FZ, Patel R, Yan C, et al. NADPH oxidase is involved in angiotensin II-induced apoptosis in H9C2 cardiac muscle cells: Effects of apocynin. Free Radical Biology Medicine, 2006,40 : 236– 246.
[97]、Lassegue B, Sorescu D, Szocs K, et al. Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res, 2001, 88: 888-894.
[98]、毛张凡,孙宗全,杜心灵。五甲基槲皮素对血管紧张素Ⅱ致大鼠心肌纤维化的作用。中国药理学通报,2009,25(8):1103-1107.
1 Neri Serneri GG, Boddi M, Coppo M, et al. Evidence for the existence of a functional cardiac renin-angiotensin system in humans.Circulation,1996;94(8):1886–1893.
2 Tsai CT, Lai LP, Hwang JJ,et al.Renin-angiotensin system component expression in the HL-1 atrial cell line and in a pig model of atrial fibrillation [J]. J Hypertens,2008 Mar;26(3):570-82.
3 Arakawa K, Urata H. Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension,2000; 36(4): 638–641.
4 Urata H, Nishimura H, Ganten D. Chymase-dependent angiotensin II forming systems in humans. Am J Hypertens,1996. 9(3): 277–284.
5 Donoghue M, Hsieh F, Baronas E, et al .A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res, 2000;87(5): E1–E9,.
6 Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem, 2002;277(17): 14838–14843.
7 Santos RA, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1-7): an update. Regul Pept, 2000;91(1-3): 45–62.
8 Loot AE, Roks AJ, Henning RH, et al. Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats.Circulation, 2002; 105(13): 1548–1550.
9 Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature , 2002;417(6891): 822–828.
10 Danilczyk U, Penninger JM. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res, 2006; 98(4): 463–471.
11 Ferrario CM, Chappell MC. Novel angiotensin peptides. Cell Mol Life Sci, 2004; 61(21): 2720–2727.
12 Iyer SN, Ferrario CM, Chappell MC. Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the reninangiotensin system. Hypertension, 1998; 31(1 Pt 2): 356–361.
13 Lindpaintner K, Ganten D. The cardiac renin-angiotensin system: an appraisal of present experimental and clinical evidence. Circ Res, 1991; 68(4): 905–921.
14 Dzau VJ, Re R. Tissue angiotensin system in cardiovascular medicine. A paradigmshift? Circulation, 1994; 89(1): 493–498.
15 Von Lutterotti N, Catanzaro DF, Sealey JE, et al. Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence. Circulation, 1994; 89(1): 458–470.
16 Li L, Wang YM, Li ZZ, et al. Local RAS and inflammatory factors are involved in cardiovascular hypertrophy in spontaneously hypertensive rats. Pharmacol Res, 2008; 58(3-4):196-201.
17 Oliveira EM, Sasaki MS, Cerêncio M, et al. Local renin-angiotensin system regulates left ventricular hypertrophy induced by swimming training independent of circulating renin: a pharmacological study [J]. J Renin Angiotensin Aldosterone Syst, 2009 Mar;10(1):15-23.
18 Widdop RE, Jones ES, Hannan RE, et al. Angiotensin AT2 receptors: cardiovascular hope or hype. Br J Pharmacol,2003; 140(5): 809-824.
19 van Esch JH, Schuijt MP, Sayed J, et al. AT2 receptor-mediated vasodilation in the mouse heart depends on AT1A receptor activation. Br J Pharmacol,2006 Jun;148(4):452-458.
20 Kurisu S, Ozono R, Oshima T, et al.Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension, 2003, 41(1):99–107
21 Metcalfe BL, Huentelman MJ, Parilak LD, et al. Prevention of cardiac hypertrophy by angiotensin II type-2 receptor gene transfer. Hypertensin, 2004 Jun;43(6):1233-1238.
22 Schhnec JM,Hsueh WA,Angiotensin 1,adhesion,and cardiac fibrosis?Cardiovasc Res,2000,46:264～268.
23 Kim S, Iwao H. Molecular and cellar mechanisms of angiotensinⅡ-mediated cardiovascular and renal diseases. Pharmacolngical Reviews, 2000; 52: ll-34.
24 Hagaki J, Aoki M, Morishita, et a1. In vivo evidence of the importance of cardiac angiotensin—converting enzyme in the pathngenesis of cardiac hypertrophy. Arterioscler Thromb Vase Biol, 2000; 20:428-434.
25 Diep QN, El Mabrouk M, Yue P, et al.Effect of AT(1) receptor blockade on cardiac apoptosis in angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol, 2002 May; 282(5):H1635-1641.
26 Chen K, Mehta J L, Li Dy, et al. Transforming Growth Factor ? Receptor Endoglin Is Expressed in Cardiac Fibroblasts and Modulates Profibrogenic Actions of Angiotensin II. Circ Res, 2004; 95(12):1167-1173.
27 Yamakawa T, Tanaka S, Kamei J,et al. Phosphatidylinositol 3-kinase in angiotensin II-induced hypertrophy of vascular smooth muscle cells. European Journal of Pharmacology, 2003; 478(1): 39– 46.
28 Murasawa S, Mori Y, Nozawa Y, et al. Angiotensin II type 1 receptor-inducedextracellular signalregulated protein kinase activation is mediated by Ca2+/calmodulindependent transactivation of epidermal growth factor receptor. Circ Res, 1998;82(12):1338–1348.
29 Zhao Yl, Liu J, Lia L,et al. Role of Ras/PKCζ/MEK/ERK1/2 signaling pathway in angiotensin II-induced vascular smooth muscle cell proliferation. Regulatory Peptides, 2005;128(1): 43– 50.
30 Oudot A , Vergely C, Ecarnot-Laubriet A, et al. Angiotensin II activates NADPH oxidase in isolated rat hearts subjected to ischaemia–reperfusion. European Journal of Pharmacology , 2003;462(1-3) :145-154.
31 Wu SL, Gao JP, Ohlemeyer C, et al. Activation of AP-1 through reactive oxygen species by angiotensin II in rat cardiomyocytes. Free Radical Biology & Medicine, 2005; 39(12):160 -1610.
32 Berry C, Anderson N, Kirk AJ,et al. Renin angiotensin system inhibition is associated with reduced free radical concentrations in arteries of patients with coronary heart disease. Heart. 2001 Aug;86(2):217-220.
33 Nishida M, Tanabe S, Maruyama Y, et al. G alpha 12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes. J Biol Chem, 2005 May;280(18):18434-1841.
34 Wenzel S, Taimor G, Riper HM, et al.Redox-sensitive intennediates mediate angiotensinⅡ-induced p38 MAPkinase activation, AP-l binding activity, and TGF-βto expression in adult ventfieular cardiomyocytes[J]. FASEB J, 200l;15(12):2291-2293.
35 Ruiz-Ortega M, Ruperez M, Esteban V, et a1. Molecular mechanisms of angiotensin lI-induced vascular injury[J]. Curr Hypertens Rep, 2003;5(1):73-79.
[2]、高婷,吴锡南。某钢铁公司轧钢工人噪声暴露与听力损失的调查[J].中国药物与临床, 2010,l0(9):1017-1019.
[3]、尹嘉才,胡正元,周笃强,等.全军武器装备噪声的现状与分析[M].全军噪声协作组,1992:1-3.
[4]、Skinner C, Grimwood C. The National Noise Incidence Study 2000/2001 (United Kingdom): Vol 1 - Noise levels. BRE report 206344f, 2002.
[5]、Berglund B, Lindvall T, Schwela D, et al. Guidelines for community noise. 2000:20-34.
[6]、世界卫生组织,心血管疾病。实况报道,第317号(2011年1月)。http://www.who.int/mediacentre/factsheets/fs317/zh/index.html.
[7]、Gerber SE, Mulac A, Lamb ME. The cardiovascular response to acoustic stimuli. Audiology, 1977 Jan-Feb;16(1):1-10.
[8]、Idzior-Walu? B. Coronary risk factors in men occupationally exposed to vibration and noise. Eur Heart , 1987 Oct;8(10):1040-1046.
[9]、Babisch W, Gallacher JE, Elwood PC, et al. Traffic noise and cardiovascular risk. The Caerphilly study, first phase. Outdoor noise levels and risk factors. Arch Environ Health, 1988 Nov-Dec;43(6):407-414.
[10]、Ising H, Rebentisch E, Poustka F, et al. Annoyance and health risk caused by military low-altitude flight noise. Int Arch Occup Environ Health, 1990;62(5):357-363.
[11]、Haralabidis AS, Dimakopoulou K, Vigna-Taglianti F, et al. Acute effects of night-time noise exposure on blood pressure in populations living near airports. Eur Heart J, 2008 Mar;29(5):658-664.
[12]、Jarup L, Babisch W, Houthuijs D, et al. Hypertension and exposure to noise near airports: The HYENA study. Environ Health Perspect, 2008;116(3):329-333.
[13]、Kempen EE,Kruize H,Boshuizen HC,et al.The association between noise exposure and blood pressure and ischemic heart disease: a meta-analysis. Environ Health Perspect, 2002;110(3): 307-317.
[14]、Babisch W, Elwood PC, Ising H, et al. Traffic noise as a risk factor for myocardial infarction. Schriftenr Ver Wasser Boden Lufthyg, 1993;88:135-166.
[15]、Ising H, Kruppa B. Health effects caused by noise : Evidence in the literature from the past 25 years. Noise Health 2004;6(22):5-13.
[16]、Abbate C, Giorgianni C, MunaòF, et al. Effects of noise on functional cardiovascular parameters: a follow-up study. G Ital Med Lav Ergon, 2002 ;24(1):43-48.
[17]、Aydin Y, Kaltenbach M. Noise perception, heart rate and blood pressure in relation to aircraft noise in the vicinity of the Frankfurt airport. Clin Res Cardiol, 2007; 96(6):347-358.
[18]、Babisch W.Transportation noise and cardiovascular risk: Updated review and synthesis of epidemiological studies indicate that the evidence has increased.Noise Health, 2006 Jan-Mar;8(30):1-29.
[19]、Gan WQ, Davies HW, Demers PA. Exposure to occupational noise and cardiovascular disease in the United States: the National Health and Nutrition Examination Survey 1999-2004. Occup Environ Med, 2011 Mar;68(3):183-90.
[20]、Peterson EA, Augenstein JS, Hazelton CL, et al. Some cardiovascular effects of noise. J Aud Res, 1984, 24(1): 35-62.
[21]、Gesi M, Fornai F, Lenzi P, et al. Ultrastructural localization of calcium deposits in rat myocardium after loud noise exposure. J Submicrosc Cytol Pathol. 2000 ;32(4):585-590.
[22]、Okada A, Ariizumi M,Okamoto G. Study on the mechanism of the appearance of noise effects. Eur J Appl Physiol Occup Physiol, 1985,53(4):364-367.
[23]、Turkkan JS,Hienz RD,Harris AH.Novel long-term cardiovascular effects of industrial noise. Physiol Behav, 1984, Jul,33(1):21-26.
[24]、Maschke C,Rupp T,Hecht K. The influence of stressors on biochemical reactions-a review of present scientific findings with noise. Int J Hyg Environ Health,2000,203(1): 45-53.
[25]、Windle RJ, Wood SA, Lightman SL,et al. The pulsatile characteristics of Hypothalamo-Pituitary-Adrenal activity in female lewis and fischer 344 Rats and its relationship to differential stress responses.Endocr, 1998,139(10): 4044-4052.
[26]、Boer SF,Slangen JL,Gugten JV. Adaptation of plasma catecholamine and corticosterone responses to short-term repeated noise stress in rats. Physiol Behav,1988;44(2):273-280.
[27]、Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J, 1984,108(1):188-193.
[28]、Ising H,Babisch W,Kruppa B. Noise-Induced Endocrine Effects and Cardiovascular Risk. Noise Health. 1999;1(4):37-48.
[29]、Ferrario CM. Role of Angiotensin II in Cardiovascular Disease-Therapeutic Implications of More Than a Century of Research . JRAAS, 2006,7(1):3-14.
[30]、Ibrahim MM. RAS inhibition in hypertension. J Hum Hypertens, 2006;20(2):101-8.
[31]、周正谋,孙阿成,赵云涛,等.强噪声短期暴露对大鼠类内洋地黄素和血管紧张素Ⅱ的影响.中华劳动卫生职业病杂志,1995,13(6): 341-342
[32]、张素珍,徐永,万瑜,等。应激大鼠血浆与肾上腺组织血管紧张素Ⅱ的水平及ANGmRNA在肾上腺组织中的表达。广东医学院学报,2002,20(2):87-88
[33]、Sim?es MR, Ribeiro Júnior RF, Vescovi MV, et al. Acute lead exposure increases arterial pressure:role of the rennin-angiotensin system. PLoS One, 2011 Apr 11;6(4):e18730-18736.
[34]、Dostal DE, Baker KM. The Cardiac Renin-Angiotensin System : Conceptual, or a Regulator of Cardiac Function? Circ Res, 1999;85:643-650.
[35]、Chan WP, Fung ML, Nobiling R, et al. Activation of local renin-angiotensin system by chronic hypoxia in rat pancreas. Molecular and Cellular Endocrinology, 2000; 160:107–114.
[36]、Thomasa MA, Fleissner G, Sto¨hr M, et al. Localization of components of the renin–angiotensin system in the suprachiasmatic nucleus of normotensive Sprague–Dawley rats Part A. Angiotensin I/II, a light and electron microscopic study. Brain Research, 2004;1008:212–223.
[37]、Leung PS, Fung ML, Tam MS. Renin–angiotensin system in the carotid body .The International Journal of Biochemistry & Cell Biology, 2003; 35: 847–854.
[38]、Dostal DE, Rothblum KN, Chernin MI, et al. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in the neonatal rat heart. Am Physiol, 1992: 263:C838-850.
[39]、Dostal DE, Baker KM. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res, 1999; 85:643–650.
[40]、Li L, Yi-Ming W, Li ZZ, et al. Local RAS and inflammatory factors are involved in cardiovascular hypertrophy in spontaneously hypertensive rats. Pharmacol Res. 2008 Sep-Oct;58(3-4):196-201.
[41]、Oliveira EM, Sasaki MS, Cerêncio M, et al. Local renin-angiotensin system regulates left ventricular hypertrophy induced by swimming training independent of circulating renin: a pharmacological study [J]. J Renin Angiotensin Aldosterone Syst. 2009 Mar;10(1):15-23.
[42]、Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol ,2007;292:C82–97.
[43]、Whaley-Connell AT, Chowdhury NA, Hayden MR, et al. Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat. Am J Physiol Renal Physiol, 2006; 291:F1308-F1314.
[44]、Zou XJ, Yang L, Yao SL. Propofol depresses angiotensin II-inducedcardiomyocyte hypertrophy in vitro. Exp Biol Med (Maywood), 2008; 233(2): 200-208.
[45]、Nakagam H, Takemoto M, Liao LK. NADPH oxidase-derived superoxide anion mediates angiotensinⅡ-induced cardiac hypertrophy. J Mell Cell Cardiol,2003; 35(7):851-859.
[46]、Griendling KK, Minieri CA, Ollerenshaw JD, et al. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res, 1994;74(6):1141–8.
[47]、Oudot A, Vergely C, Ecarnot-Laubriet A, et al. Angiotensin II activates NADPH oxidase in isolated rat hearts subjected to ischaemia–reperfusion. European Journal of Pharmacology, 2003; 462:145– 154.
[48]、Kawahara T, Quinn MT, Lambeth JD, et al. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evolutionary Biology, 2007; 7:109-129.
[49]、Selemidis s, Sobey CG, Wingler K, et al. NADPH oxidases in the vasculature: Molecular features, roles in disease and pharmacological inhibition. Pharmacology Therapeutics, 2008;120: 254-291.
[50]、Matutea JD, Ariasa AA, Dinauer, MC, et al. p40phox: The last NADPH oxidase subunit. Blood Cells Molecules Diseases, 2005; 35: 291-302.
[51]、Lavigne MC, Malech HL, Holland, SM, et al. Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells. Circulation, 2001;104: 79–84.
[52]、Touyz RM, Chen X, Tabet F, et al. Expression of a functionally active gp91phox-containing neutrophiltype NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res, 2002; 90:1205-1213.
[53]、Hassanain HH, Gregg D, Marcelo ML, et al. Hypertension caused by transgenic overexpression of Rac1. Antioxid Redox Signal, 2007; 9: 91-100.
[54]、Livak KJ,Schmittgen TD.Analysis of relative gene expression data using real- time quantitative PCR and the 2 -⊿⊿CT method[J].Methods,2001,25(4):402—408.
[55]、Sobotova L, Jurkovicova J, Stefanikova Z, et al. Community response to environmental noise and the impact on cardiovascular risk score. Sci Total Environ, 2010 Feb,408(6):1264-70.
[56]、Berglund B, Lindvall T, Schwela D, et al. Guidelines for Community Noise[M]. World Health Organisation 2000;28-29.
[57]、Gerber SE, Mulac A, Lamb ME. The cardiovascular response to acoustic stimuli. Audiology. 1977;16(1):1-10.
[58]、Andrén L, Hansson L, Bj?rkman M, et al. Hemodynamic and hormonal changes induced by noise. Acta Med Scand Suppl. 1979;625:13-18.
[59]、Andrén L, Lindstedt G, Bj?rkman M, et al. Effect of noise on blood pressure and 'stress' hormones. Clin Sci (Lond) 1982;62(2):137-141.
[60]、Babisch W,Fromme H,Beyer A,et al.Increased catecholamine levels in urine in subjects exposed to road traffic noise:the role of stress homones in noise research.Environ Int,2001,26(7-8):475-481.
[61]、Paparelli A, Pellegrini A, Lenzi P, et al. Ultrastructural changes in atrial tissue of young and aged rats submitted to acute noise stress. J Submicrosc Cytol Pathol 1995;27(1):137-42.
[62]、Ivanovich E, Antov G. Enzyme changes in the myocardium of experimental animals exposed to noise of various intensities. Probl Khig 1981;6:9-14.
[63]、Softowa E, Malewa E, Zlatewa M. Histomorphological changes in the myocardium of experimental animals in long-term exposure to intense industrial noise. Zentralbl Allg Pathol 1983;127(1-2):85-89.
[64]、Lenzi P, Frenzilli G, Gesi M, et al. DNA damage associated with ultrastructural alterations in rat myocardium after loud noise exposure. Environ Health Perspect. 2003;111(4):467-471.
[65]、Gesi M, Pellegrini A, Lenzi P, et al. Effects of newly-developed benzodiazepine ligands on noise-induced mitochondrial damage in the rat. Ann Anat. 2000;182(4):311-318.
[66]、Bao G, Metreveli N, Fletcher EC, et al. Acute and chronic blood pressure response to recurrent acoustic arousal in rats.Am J Hypertens. 1999 May;12(5):504-510.
[67]、Marciniak W, Rodriguez E, Olszowska K, et al. Echocardiographic evalution in 485 aeronautical workers exposed to different noise environments. Aviat Space Environ Med, 1999, 70(3 Pt 2): A46-53.
[68]、Soldani P, Pellegrini A, Gesi M, et al. SEM/TEM investigation of rat cardiac subcellular alterations induced by changing duration of noise stress. Anat Rec, 1997, 248(4): 521-532.
[69]、Borutaite V, Vrown GC. Mitochondria in apoptosis of ischemic heart. FEBS Lett ,2003 Apr,541(1-3):1-5.
[70]、Weiss JN, Korge P, Honda HM, et al. Role of the mitochondrial permeability transition in myocardial disease. Circ Res, 2003,93(4):292-301.
[71]、Yamashita D, Jiang HY, Schacht J, et al. Delayed production of free radicals following noise exposure. Brain Res ,2004, 1019 (1–2): 201–209.
[72]、Uran SL, Caceres LG, Guelman LR. Effects of loud noise on hippocampal and cerebellar-related behaviors. Role of oxidative state. Brain Research, 2010(1361):102-114.
[73]、Khullar M, Relan V, Sherawat BS.Antioxidant activities and oxidative stress by- products in human hypertension[J].Hypertension, 2004, 43(2):7-8.
[74]、Kim YH, Lim DS, Lee JH, et a1.Gene expression profiling of oxidative stress on atrial fibrillation in humans[J].Exp Mol Med, 2003, 35(5): 336-349.
[75]、Saha S, Gandhi A, Das S, et al. Effect of noise stress on some cardiovascular parameters and audiovisual reaction time. Indian J Physiol Pharmacol, 1996, 40(1): 35-40.
[76]、Regecova V, Kellerova E. Effects of urban noise pollution on blood pressure and heart rate in preschool children. J Hypertens, 1995, 13(4) : 405-412.
[77]、唱斗,梁武,王生.高频稳态噪声对心血管系统影响的调查.中国职业医学, 2003, 30(2):25-27.
[78]、Dzau VJ, Ellison KE, Brody T, et al. A comparative study of the distributions of renin and angiotensinogen messenger ribonucleic acids in rat and mouse tissues. Endocrinology1987;120:2334–2338.
[79]、Dostal DE, Rothblum KC, Chernin MI, et al. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in neonatal rat heart. Am J Physiol. 1992;263:C838–C863.
[80]、Dostal DE, Rothblum KC, Baker KM. An improved method for absolute quantification of mRNA using multiplex polymerase chain reaction: determination of renin and angiotensinogen mRNA levels in various tissues. Anal Biochem. 1994;223:239–250.
[81]、Tsai CT, Lai LP, Hwang JJ,et al.Renin-angiotensin system component expression in the HL-1 atrial cell line and in a pig model of atrial fibrillation [J]. J Hypertens,2008;26(3):570-82.
[82]、Arakawa K, Urata H. Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension,2000; 36(): 638–641.
[83]、Urata H, Nishimura H, Ganten D. Chymase-dependent angiotensin II forming systems in humans. Am J Hypertens,1996. 9: 277–284,
[84]、Von Lutterotti N, Catanzaro DF, Sealey JE, et al. Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence. Circulation1994; 89: 493–498.
[85]、Kobori H, Ichihara A, Suzuki H, et al. Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism. Am J Physiol. 1997;273:H593–H599.
[86]、Mazzolai L, Nussberger J, Jean-Francois A, et al. Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension. 1998; 31:1324–1330.
[87]、Amaral SL, Papanek PE, Greene AS. Angiotensin II and VEGF are involved in angiogenesis induced by short-term exercise training. Am J Physiol Heart Circ Physiol, 2001, 281(3): H1163–H1169.
[88]、Chung IM, Kim YM, Yoo MH, et al. Immobilization stress induces endothelial dysfunction by oxidative stress via the activation of the angiotensin II/its type I receptor pathway. Atherosclerosis, 2010, 213(1): 109–114.
[89]、Wright JW, Dengerink HA, Miller JM, et al. Potential role of angiotensin II in noise-induced increases in inner ear blood flow. Hear Res, 1985,17(1):41-6.
[90]、Nakagami H , Takemoto M , Liao JK, et al. NADPH oxidase-derived superoxide anion mediates angiotensin II-induced cardiac hypertrophy.J Mol Cell Cardiol, 2003 July, 35(7): 851–859.
[91]、Lavigne MC, Malech HL, Holland SM, et al. Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells. Circulation,2001, 104: 79–84.
[92]、Heymes C, Bendall JK, Ratajczak P, et al. Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol, 2003, 41:2164– 2171.
[93]、Samuel CD, Nyssa EH, Louise AM, et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage:role of the NADPH and xanthine oxidases.Circulation,2005,112:1266-1273.
[94]、Mol1nau H, Wendt M,Szocs K, et al. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling .Circ Res, 2002,90(4):E58一E65
[95]、Ungvari Z, Csiszar A, Huang A, et al. A high pressure induces superoxide production in isolated arteries via protein kinase C一dependent activation of NAD(P) H oxidase.Circulation, 2003 ,108 (10) ;1253一1258
[96]、Qin FZ, Patel R, Yan C, et al. NADPH oxidase is involved in angiotensin II-induced apoptosis in H9C2 cardiac muscle cells: Effects of apocynin. Free Radical Biology Medicine, 2006,40 : 236– 246.
[97]、Lassegue B, Sorescu D, Szocs K, et al. Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res, 2001, 88: 888-894.
[98]、毛张凡,孙宗全,杜心灵。五甲基槲皮素对血管紧张素Ⅱ致大鼠心肌纤维化的作用。中国药理学通报,2009,25(8):1103-1107.
1 Neri Serneri GG, Boddi M, Coppo M, et al. Evidence for the existence of a functional cardiac renin-angiotensin system in humans.Circulation,1996;94(8):1886–1893.
2 Tsai CT, Lai LP, Hwang JJ,et al.Renin-angiotensin system component expression in the HL-1 atrial cell line and in a pig model of atrial fibrillation [J]. J Hypertens,2008 Mar;26(3):570-82.
3 Arakawa K, Urata H. Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension,2000; 36(4): 638–641.
4 Urata H, Nishimura H, Ganten D. Chymase-dependent angiotensin II forming systems in humans. Am J Hypertens,1996. 9(3): 277–284.
5 Donoghue M, Hsieh F, Baronas E, et al .A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res, 2000;87(5): E1–E9,.
6 Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem, 2002;277(17): 14838–14843.
7 Santos RA, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1-7): an update. Regul Pept, 2000;91(1-3): 45–62.
8 Loot AE, Roks AJ, Henning RH, et al. Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats.Circulation, 2002; 105(13): 1548–1550.
9 Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature , 2002;417(6891): 822–828.
10 Danilczyk U, Penninger JM. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res, 2006; 98(4): 463–471.
11 Ferrario CM, Chappell MC. Novel angiotensin peptides. Cell Mol Life Sci, 2004; 61(21): 2720–2727.
12 Iyer SN, Ferrario CM, Chappell MC. Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the reninangiotensin system. Hypertension, 1998; 31(1 Pt 2): 356–361.
13 Lindpaintner K, Ganten D. The cardiac renin-angiotensin system: an appraisal of present experimental and clinical evidence. Circ Res, 1991; 68(4): 905–921.
14 Dzau VJ, Re R. Tissue angiotensin system in cardiovascular medicine. A paradigmshift? Circulation, 1994; 89(1): 493–498.
15 Von Lutterotti N, Catanzaro DF, Sealey JE, et al. Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence. Circulation, 1994; 89(1): 458–470.
16 Li L, Wang YM, Li ZZ, et al. Local RAS and inflammatory factors are involved in cardiovascular hypertrophy in spontaneously hypertensive rats. Pharmacol Res, 2008; 58(3-4):196-201.
17 Oliveira EM, Sasaki MS, Cerêncio M, et al. Local renin-angiotensin system regulates left ventricular hypertrophy induced by swimming training independent of circulating renin: a pharmacological study [J]. J Renin Angiotensin Aldosterone Syst, 2009 Mar;10(1):15-23.
18 Widdop RE, Jones ES, Hannan RE, et al. Angiotensin AT2 receptors: cardiovascular hope or hype. Br J Pharmacol,2003; 140(5): 809-824.
19 van Esch JH, Schuijt MP, Sayed J, et al. AT2 receptor-mediated vasodilation in the mouse heart depends on AT1A receptor activation. Br J Pharmacol,2006 Jun;148(4):452-458.
20 Kurisu S, Ozono R, Oshima T, et al.Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension, 2003, 41(1):99–107
21 Metcalfe BL, Huentelman MJ, Parilak LD, et al. Prevention of cardiac hypertrophy by angiotensin II type-2 receptor gene transfer. Hypertensin, 2004 Jun;43(6):1233-1238.
22 Schhnec JM,Hsueh WA,Angiotensin 1,adhesion,and cardiac fibrosis?Cardiovasc Res,2000,46:264～268.
23 Kim S, Iwao H. Molecular and cellar mechanisms of angiotensinⅡ-mediated cardiovascular and renal diseases. Pharmacolngical Reviews, 2000; 52: ll-34.
24 Hagaki J, Aoki M, Morishita, et a1. In vivo evidence of the importance of cardiac angiotensin—converting enzyme in the pathngenesis of cardiac hypertrophy. Arterioscler Thromb Vase Biol, 2000; 20:428-434.
25 Diep QN, El Mabrouk M, Yue P, et al.Effect of AT(1) receptor blockade on cardiac apoptosis in angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol, 2002 May; 282(5):H1635-1641.
26 Chen K, Mehta J L, Li Dy, et al. Transforming Growth Factor ? Receptor Endoglin Is Expressed in Cardiac Fibroblasts and Modulates Profibrogenic Actions of Angiotensin II. Circ Res, 2004; 95(12):1167-1173.
27 Yamakawa T, Tanaka S, Kamei J,et al. Phosphatidylinositol 3-kinase in angiotensin II-induced hypertrophy of vascular smooth muscle cells. European Journal of Pharmacology, 2003; 478(1): 39– 46.
28 Murasawa S, Mori Y, Nozawa Y, et al. Angiotensin II type 1 receptor-inducedextracellular signalregulated protein kinase activation is mediated by Ca2+/calmodulindependent transactivation of epidermal growth factor receptor. Circ Res, 1998;82(12):1338–1348.
29 Zhao Yl, Liu J, Lia L,et al. Role of Ras/PKCζ/MEK/ERK1/2 signaling pathway in angiotensin II-induced vascular smooth muscle cell proliferation. Regulatory Peptides, 2005;128(1): 43– 50.
30 Oudot A , Vergely C, Ecarnot-Laubriet A, et al. Angiotensin II activates NADPH oxidase in isolated rat hearts subjected to ischaemia–reperfusion. European Journal of Pharmacology , 2003;462(1-3) :145-154.
31 Wu SL, Gao JP, Ohlemeyer C, et al. Activation of AP-1 through reactive oxygen species by angiotensin II in rat cardiomyocytes. Free Radical Biology & Medicine, 2005; 39(12):160 -1610.
32 Berry C, Anderson N, Kirk AJ,et al. Renin angiotensin system inhibition is associated with reduced free radical concentrations in arteries of patients with coronary heart disease. Heart. 2001 Aug;86(2):217-220.
33 Nishida M, Tanabe S, Maruyama Y, et al. G alpha 12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes. J Biol Chem, 2005 May;280(18):18434-1841.
34 Wenzel S, Taimor G, Riper HM, et al.Redox-sensitive intennediates mediate angiotensinⅡ-induced p38 MAPkinase activation, AP-l binding activity, and TGF-βto expression in adult ventfieular cardiomyocytes[J]. FASEB J, 200l;15(12):2291-2293.
35 Ruiz-Ortega M, Ruperez M, Esteban V, et a1. Molecular mechanisms of angiotensin lI-induced vascular injury[J]. Curr Hypertens Rep, 2003;5(1):73-79.