Pyk2信号通路在压力超负荷大鼠心肌肥厚中的作用及阿托伐他汀、伊贝沙坦的干预研究

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英文题名：Effects of Atorvastatin and Irbesartan on Pressure Overload-Induced Cardiac Hypertrophy in Rats: Role of the Pyk2 Signalling Pathway 作者：潘闽 论文级别：博士 学科专业名称：内科学 中文关键词：富含脯氨酸的酪氨酸激酶2 ; Rac-1 ; 心肌肥厚 ; 阿托伐他汀 ; 伊贝沙坦 ; 活性氧 英文关键词：Proline-rich tyrosine kinase 2 (Pyk2) ; Rac-1 ; left ventricular hypertrophy ; Atorvastatin ; Irbesartan ; Reactive oxygen species 学位年度：2007 导师：刘志华 ; 蒋文平 学科代码：100201 学位授予单位：苏州大学 论文提交日期：2007-05-01

摘要

【目的】心肌肥厚是心肌细胞对外界和(或)内在刺激的一种适应性反应。虽然心肌肥厚是心脏为维持心功能的一种有效的代偿机制,但长期的心肌肥厚可导致心肌缺血、心律失常、心力衰竭和猝死。富含脯氨酸的酪氨酸激酶2(proline-rich tyrosine kinase 2, Pyk2)是一种能被细胞内钙浓度增高及多种刺激信号激活的具有明显的酪氨酸激酶和自身激酶活性的信号分子,其调节的下游信号通路包括MAPK级联、磷脂酰肌醇3激酶(PI3K)等。本研究建立压力负荷左室肥厚模型,观察Rac1、Pyk2基因及蛋白的表达,探讨Pyk2/Rac1通路在左室肥厚心肌细胞中的作用以及阿托伐他汀、伊贝沙坦干预对其的影响。
     【方法】体重180-225g的雄性SD大鼠随机分为5组。A组为假手术组,其余4组行腹主动脉缩窄术建立压力负荷左室肥厚模型,B组为阿托伐他汀干预组,术前一周开始给予5 mg·kg-1·d-1灌胃,至术后4周;C组为伊贝沙坦干预组,术前一周开始给予20 mg·kg-1·d-1灌胃,至术后4周;D组为阿托伐他汀与伊贝沙坦联合用药组;E组为非药物组(左室肥厚模型组),灌胃器经口同时间给予等体积生理盐水。术后4周检测各组血流动力学参数,然后处死动物、制取标本。测左室质量指数(LVMI),病理切片染色后行光镜检查,并测心肌细胞横径和胶原容积百分比; 2’,7’-二氯双氢荧光素双乙酸酯(DCFH-DA)荧光探针检测细胞内活性氧(ROS)水平,RT-PCR测Rac1 mRNA、Pyk2 mRNA表达,Western blot技术检测Rac1蛋白、Pyk2及其磷酸化蛋白表达。
     【结果】(1)术后4周时左室肥厚模型组LVMI、心肌细胞横径及胶原容积指数以及ROS水平较假手术组均显著升高(P<0.05-0.01);(2)阿托伐他汀以及伊贝沙坦干预后LVMI、心肌细胞横径、胶原容积指数及ROS水平均显著低于左室肥厚模型组(P<0.05-0.01),联合用药组LVMI及ROS水平显著低于各单药组(P<0.05-0.01)。(3)术后4周时左室肥厚模型组Rac-1 mRNA及蛋白表达显著高于假手术组(P<0.05-0.01),Pyk2 mRNA及蛋白表达也显著高于假手术组(P<0.05-0.01),并且Pyk2 Tyr402蛋白表达、Pyk2 Tyr402蛋白与总Pyk2蛋白的比值均显著高于假手术组(P<0.05),直线相关分析表明Pyk2 mRNA表达与左室质量指数(LVMI)存在正相关性(P<0.05)。(4)阿托伐他汀干预组及伊贝沙坦干预组Pyk2 mRNA及蛋白表达、Pyk2 Tyr402蛋白表达、Rac1 mRNA及蛋白表达均显著低于心肌肥厚模型组(P<0.05-0.01)。而联合治疗组Pyk2 mRNA、Rac-1 mRNA及Pyk2 Tyr402蛋白表达水平显著低于各单独用药组(P<0.05-0.01)。
     【结论】①氧化应激在主动脉缩窄压力负荷左室心肌肥厚中起重要作用。②Pyk2/ Rac-1信号通路与心肌肥厚发生发展密切相关,Pyk2可能是抗心肌肥厚治疗的一个新的靶点。③阿托伐他汀及伊贝沙坦均能有效缓解压力负荷所致的左室肥厚。其抗心肌肥厚作用至少部分是通过下调Pyk2/Rac-1表达以及细胞内ROS水平实现的;而两药联用较各自单用更有利于改善心肌肥厚。
【Objective】Cardiac hypertrophy is one of the major adaptive responses to various extracellular stimuli, including hemodynamic overload (mechanical stress) and neurohumoral factors. On the other hand, cardiac hypertrophy is also known as a strong predictor for mortality and morbidity, and the most important single risk factor for heart failure. Despite numerous studies have been performed, the molecular mechanisms underlying cardiomyocyte hypertrophy, however, remain unclear. On the other hand, a lot of intracellular signaling pathways have been found to play important roles in hypertrophic processes of cardiomyocytes. The proline-rich tyrosine kinase 2 (Pyk2), is tyrosine phosphorylated and activated in response to elevation of [Ca2+]i or various stress signals. The signaling pathways downstream of the Pyk2 activation include MAPK cascades and phosphoinositide-3 kinase (PI3K)/Akt. This study is designed to investigated whether pressure overload augmented the expression and phosphorylation of Pyk2 in left ventricular myocardium developing hypertrophy in rats, we also investigated the effects of Atorvastatin and Irbesartan on Pyk2/Rac1 signalling pathway in pressure overload-induced cardiac hypertrophy.
     【Methods】Suprarenal abdominal aortic coarctation was performed to create pressure overload induced left ventricular hypertrophy model in rats. Rats were randomly assigned into 5 groups: 1) Sham group; 2) Atorvastatin (5 mg·kg-1·d-1) given orally by gastric gavage for 4 weeks; 3) Irbesartan (20 mg·kg-1·d-1) given orally by gastric gavage for 4 weeks; 4) Combining treatment group with Atorvastatin (5 mg·kg-1·d-1) and Irbesartan (20 mg·kg-1·d-1) given orally by gastric gavage for 4 weeks; and 5)Vehicle group. Before the animals were euthanized 4 weeks after surgery, hemodynamics parameters were recorded by carotid artery catheterization. Stained pathological section was observed under light microscope to measure cardiomyocyte diameter transversa and collagen volume fraction. Intracellular reactive oxygen species (ROS) levels were measured using 2′,7′-dichlorofluorescein (DCF) diacetate probes. Rac1 mRNA and Pyk2 mRNA expression were detected by RT-PCR, and their proteins as well as Pyk2 Tyr402 protein expression were assayed by Western blot.
     【Results】①All banded groups had higher LVMI, cardiomyocyte diameter transversa and collagen volume fraction than that in sham group, all banded groups also had higher intracellular ROS levels(P<0.05-0.01), and LVMI had a linear correlation with the level of ROS in vehicle group(P<0.05). Atorvastatin and Irbesartan had effective impact on attenuation of the increasing of these parameters(P<0.05-0.01).②Rac-1 and Pyk2 mRNA expression, as well as Rac-1, Pyk2 and Pyk2 Tyr402 protein expression were statistically increased in all banded groups than that in sham group(P<0.05-0.01). There is a linear correlation between LVMI and Pyk2 mRNA expression both in sham group and vehicle group(P<0.05-0.01).③Atorvastatin and Irbesartan groups had lower Rac-1 and Pyk2 mRNA expression, as well as Rac-1, Pyk2 and Pyk2 Tyr402 protein expression than that in vehicle group(P<0.05-0.01).④Compared with either drug alone, combined Atorvastatin and Irbesartan treatment had greater decreasing of LVMI, intracellular ROS levels, Rac-1 and Pyk2 mRNA expression, as well as Pyk2 Tyr402 protein expression(P<0.05-0.01).
     【Conclusion】①Oxidative stress plays important role in pressure overload induced left ventricular hypertrophy.②Pyk2/Rac-1 signalling pathway exert an important role in left ventricular hypertrophy progression, this may provide a potential therapeutic target for cardiac hypertrophy.③Both Atorvastatin and Irbesartan have effective impact on attenuation of pressure overload induced left ventricular hypertrophy. Part of this anti-hypertrophy effect may be attributed to their anti-oxidative properties, which was mediated by down-regulation of Pyk2/Rac-1 expression and phosphorylation. Dual therapy with Atorvastatin and Irbesartan produces an additive reduction in pressure overload induced left ventricular hypertrophy.

引文

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