调节组织免疫微环境抑制高血压心肌肥厚和心脏纤维化
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摘要
以心肌肥厚和心脏纤维化为特征的心脏异常重构是高血压心脏病的核心病理改变,是造成慢性心力衰竭的主要原因。除了神经-体液调节机制以外,免疫-炎症反应在高血压导致的心脏异常重构过程中发挥了关键作用。损伤相关模式分子(DAMPs)是组织细胞受到损伤因素刺激后以主动或被动方式释放到细胞外的一类物质,它们既能够通过模式识别受体激活先天免疫系统启动或促进炎症反应,又能够调节获得性免疫反应特别是Th1/Th2反应的极化方向影响炎症的转归。
热休克蛋白70(HSP70)在细胞内可通过分子伴侣作用维持细胞稳念,而在细胞外则能发挥DAMPs分子作用参与炎症的发生发展。因此我们想知道在压力过负荷损伤因素的刺激下,心血管组织主动或被动释放的HSP70能否作为重要的DAMPs分子介导心脏组织免疫-炎症反应最终导致心脏异常重构的发生。通过对腹主动脉缩窄(AAC)诱导的小鼠高血压模型进行研究我们发现,在压力过负荷应激状态下,心脏组织中HSP70表达升高并异常地分布于心肌细胞膜表面,血液HSP70浓度亦显著升高。热休克蛋白转录因子抑制剂虽然可以降低血液HSP70水平,改善心肌细胞膜表面HSP70的异常分布,显著抑制AAC诱导心脏纤维化,但同时却增加高血压诱导的心肌肥厚,降低心脏收缩功能,而使用抗体功能性地阻断HSP70则能在不改变动物血流动力学的前提下显著地减轻高血压诱导的心肌肥厚和心脏纤维化。进一步的研究显示,HSP70表达、释放的减少或免疫功能的阻断可显著地降低高血压诱导的心脏组织中MCP-1表达的增加及巨噬细胞的浸润升高,抑制Th2型细胞因子TGF-β1的表达。功能性阻断HSP70对心脏的保护作用可能与其抑制心脏组织中MAPK信号的活化有关。上述结果提示,在血压过负荷的刺激下,心肌细胞内、细胞外HSP70对心肌肥厚产生不同的调节作用,而只有细胞外的HSP70可作为DAMPs分子诱导心脏组织处于Th2方向的免疫微环境,促进高血压心脏纤维化的形成。
免疫—炎症反应介导内外源性致病因素引起的心血管组织纤维化和肥厚,调节异常改变的免疫—炎症反应可能是逆转心血管组织纤维化和肥厚的重要途径。卡介苗(BCG)是牛型结核杆菌经改造获得的安全有效的抗结核病疫苗,也是强大的Th1型免疫调节剂,我们发现BCG在不改变血流动力学前提下,显著减轻血压过负荷所致心脏肥厚和纤维化,这种心脏保护作用与其上调心脏组织中IFN-γ的表达,减少心脏组织2型巨噬细胞的浸润,调节心脏组织Th1/Th2平衡向Th1方向迁移有关,进一步研究发现BCG促进Th1反应的心脏保护作用可以被TLR4抑制剂而不能被DC-SIGN抑制剂所逆转,这说明TLR4信号系统的激活介导了BCG的心脏保护作用。本研究获得的结果有助于深入理解高血压心脏病发病过程中心脏异常重构的免疫病理学机制,为今后开发治疗心脏异常重构的疫苗提供了理论依据和研究线索。
Hypertension-induced chronic cardiac ventricular pressure overload leads to changes in myocardial structure and function that are referred to as myocardial remodeling, consisting of cardiomyocyte hypertrophy and cardiac fibrosis. Apart from the stimulation of neurohormones induced by hypertension, the activation of innate and adaptive immune responses participates in the pathogenesis of cardiovascular remodeling. Molecules of damage associated molecular patterns (DAMPs), which can be actively or passively released to extracellular space after initial damage induced by overload pressure, can ignite innate immune response by activating the pattern recognized receptors. Also this effect will modulate the development of adaptive immune response, especially the balance of Th1/Th2 immune responses which plays critical role in the pathogenesis of cardiac remodeling. We wondered if HSP70, which has been identified as an important molecule of DAMPs, could induce immune response in myocardium and participate in the pathogenesis of hypertension-induced cardiac hypertrophy and fibrosis. Our studies indicated that the sustained pressure overload enhanced the translocation of HSP70 to the membrane of cardiomyocyte and elevated the serum level of HSP70 in the murine model of abdominal aortic constriction (AAC). Inhibition of HSP70 expression by a specific HSP transcription inhibitor reduced the serum level of HSP70 and the abnormal distribution of HSP70 which caused an enhancement of myocardial hypertrophy but a regression of cardiac fibrosis induced by AAC. However, functional blockage of HSP70 by a specific anti-HSP70 antibody significantly attenuated pressure overload-induced cardiac hypertrophy and fibrosis with no changes in hemodynamics. These results indicated that intracellular or extracellular HSP70 mediated the different effects in the regulation of myocardial hypertrophy but only extracellular HSP70 mediated pressure overload-stimulated cardiac fibrosis. The cardiac protective effects of the anti-HSP70 antibody were largely attributed to its capability to block AAC-activated immune response in the heart, which was characterized by increasing infiltrating macrophages and increasing the expression of proinflammatory factor MCP-1 and profibrotic factor TGF-β1. Above results indicated that modulation of abnormal myocardium immune environment may be beneficial to alleviate the pressure overload-inducing cardiac remodeling. Indeed, we also found that BCG, a safe vaccine which strongly promotes Th1 immune response, could attenuate cardiac hypertrophy and fibrosis followed by AAC-induced pressure overload in murine models. BCG prevented cardiac hypertrophy by integrative activation of TLR4 signaling pathway to shift the balance of Th1/Th2 immune responses to Th1 dominant response in the myocardium. The mechanism of this cardiac protective effect was partially due to BCG-induced a decrease in the number of heart infiltrating M2- macrophages.
热休克蛋白70(HSP70)在细胞内可通过分子伴侣作用维持细胞稳念,而在细胞外则能发挥DAMPs分子作用参与炎症的发生发展。因此我们想知道在压力过负荷损伤因素的刺激下,心血管组织主动或被动释放的HSP70能否作为重要的DAMPs分子介导心脏组织免疫-炎症反应最终导致心脏异常重构的发生。通过对腹主动脉缩窄(AAC)诱导的小鼠高血压模型进行研究我们发现,在压力过负荷应激状态下,心脏组织中HSP70表达升高并异常地分布于心肌细胞膜表面,血液HSP70浓度亦显著升高。热休克蛋白转录因子抑制剂虽然可以降低血液HSP70水平,改善心肌细胞膜表面HSP70的异常分布,显著抑制AAC诱导心脏纤维化,但同时却增加高血压诱导的心肌肥厚,降低心脏收缩功能,而使用抗体功能性地阻断HSP70则能在不改变动物血流动力学的前提下显著地减轻高血压诱导的心肌肥厚和心脏纤维化。进一步的研究显示,HSP70表达、释放的减少或免疫功能的阻断可显著地降低高血压诱导的心脏组织中MCP-1表达的增加及巨噬细胞的浸润升高,抑制Th2型细胞因子TGF-β1的表达。功能性阻断HSP70对心脏的保护作用可能与其抑制心脏组织中MAPK信号的活化有关。上述结果提示,在血压过负荷的刺激下,心肌细胞内、细胞外HSP70对心肌肥厚产生不同的调节作用,而只有细胞外的HSP70可作为DAMPs分子诱导心脏组织处于Th2方向的免疫微环境,促进高血压心脏纤维化的形成。
免疫—炎症反应介导内外源性致病因素引起的心血管组织纤维化和肥厚,调节异常改变的免疫—炎症反应可能是逆转心血管组织纤维化和肥厚的重要途径。卡介苗(BCG)是牛型结核杆菌经改造获得的安全有效的抗结核病疫苗,也是强大的Th1型免疫调节剂,我们发现BCG在不改变血流动力学前提下,显著减轻血压过负荷所致心脏肥厚和纤维化,这种心脏保护作用与其上调心脏组织中IFN-γ的表达,减少心脏组织2型巨噬细胞的浸润,调节心脏组织Th1/Th2平衡向Th1方向迁移有关,进一步研究发现BCG促进Th1反应的心脏保护作用可以被TLR4抑制剂而不能被DC-SIGN抑制剂所逆转,这说明TLR4信号系统的激活介导了BCG的心脏保护作用。本研究获得的结果有助于深入理解高血压心脏病发病过程中心脏异常重构的免疫病理学机制,为今后开发治疗心脏异常重构的疫苗提供了理论依据和研究线索。
Hypertension-induced chronic cardiac ventricular pressure overload leads to changes in myocardial structure and function that are referred to as myocardial remodeling, consisting of cardiomyocyte hypertrophy and cardiac fibrosis. Apart from the stimulation of neurohormones induced by hypertension, the activation of innate and adaptive immune responses participates in the pathogenesis of cardiovascular remodeling. Molecules of damage associated molecular patterns (DAMPs), which can be actively or passively released to extracellular space after initial damage induced by overload pressure, can ignite innate immune response by activating the pattern recognized receptors. Also this effect will modulate the development of adaptive immune response, especially the balance of Th1/Th2 immune responses which plays critical role in the pathogenesis of cardiac remodeling. We wondered if HSP70, which has been identified as an important molecule of DAMPs, could induce immune response in myocardium and participate in the pathogenesis of hypertension-induced cardiac hypertrophy and fibrosis. Our studies indicated that the sustained pressure overload enhanced the translocation of HSP70 to the membrane of cardiomyocyte and elevated the serum level of HSP70 in the murine model of abdominal aortic constriction (AAC). Inhibition of HSP70 expression by a specific HSP transcription inhibitor reduced the serum level of HSP70 and the abnormal distribution of HSP70 which caused an enhancement of myocardial hypertrophy but a regression of cardiac fibrosis induced by AAC. However, functional blockage of HSP70 by a specific anti-HSP70 antibody significantly attenuated pressure overload-induced cardiac hypertrophy and fibrosis with no changes in hemodynamics. These results indicated that intracellular or extracellular HSP70 mediated the different effects in the regulation of myocardial hypertrophy but only extracellular HSP70 mediated pressure overload-stimulated cardiac fibrosis. The cardiac protective effects of the anti-HSP70 antibody were largely attributed to its capability to block AAC-activated immune response in the heart, which was characterized by increasing infiltrating macrophages and increasing the expression of proinflammatory factor MCP-1 and profibrotic factor TGF-β1. Above results indicated that modulation of abnormal myocardium immune environment may be beneficial to alleviate the pressure overload-inducing cardiac remodeling. Indeed, we also found that BCG, a safe vaccine which strongly promotes Th1 immune response, could attenuate cardiac hypertrophy and fibrosis followed by AAC-induced pressure overload in murine models. BCG prevented cardiac hypertrophy by integrative activation of TLR4 signaling pathway to shift the balance of Th1/Th2 immune responses to Th1 dominant response in the myocardium. The mechanism of this cardiac protective effect was partially due to BCG-induced a decrease in the number of heart infiltrating M2- macrophages.
引文
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