严重烧伤后缺氧和β肾上腺素能受体持续激活导致心肌损害的机制及心肌保护
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摘要
严重烧伤后心功能不全出现较早,可诱发或加重休克,成为烧伤后多器官功能不全(MODS)的重要启动因素之一[1]。在各种动物模型和人心脏中的大量研究表明不断增加的心肌细胞凋亡是心功能不全的主要原因。烧伤后心肌局部血流量迅速减少,发生缺氧损害,缺氧损害本身即可导致心肌细胞的死亡。与此同时严重烧伤引起的持续应激状态使交感-肾上腺素髓质兴奋性增加,血液儿茶酚胺上升为正常的7～8倍[2],进而持续激活心肌细胞上的β肾上腺素能受体(β-AR),最终导致心肌细胞凋亡或者坏死。因此缺氧和β肾上腺素能受体过度激活可能是严重烧伤后心肌细胞死亡的两大损伤因素。
热休克蛋白90 (HSP 90)作为一种分子伴侣,其作用是维护大量蛋白折叠和构象成熟。HSP90除了具有分子伴侣功能,还参与调节了多种细胞信号通路和细胞功能[3]。研究证明HSP90对多种凋亡诱导因子引起的心肌细胞凋亡具有保护作用。本实验首先检测了HSP90是否具有抗缺氧诱导的心肌细胞凋亡的作用。
我们建立体外培养的新生大鼠心肌细胞缺氧模型,应用HSP90的特异性抑制剂格尔德霉素(geldanamycin,GA)抑制心肌细胞HSP90活性。我们运用MTT法检测心肌细胞活力,酶联免疫(ELISA)试剂盒检测心肌细胞培养液中乳酸脱氢酶(LDH)的漏出率、TUNEL染色检测心肌凋亡率等观测多项细胞生物学指标。结果显示:缺氧引起心肌细胞膜结构破坏、细胞活力下降,并最终导致细胞凋亡;用GA抑制HSP90活性后,心肌细胞活力下降和细胞凋亡明显加剧。这些结果明确了HSP90对心肌具有抗缺氧损伤的内源性保护效应。
我们进一步探讨了HSP90抗缺氧诱导的心肌细胞凋亡的作用机制。磷脂酰肌醇3激酶/蛋白质丝氨酸苏氨酸激酶(PI3K/Akt)信号通路作为细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,在细胞内发挥着抑制凋亡、促进增殖的关键作用。PI3K/Akt信号通路能够提高心肌功能和促进心肌细胞的存活。研究提示HSP90可能是蛋白质丝氨酸/苏氨酸激酶(Akt)的上游调节分子。所以我们假设HSP90对严重烧伤后的心肌细胞的保护作用机制是通过调控PI3K/Akt通路的抗凋亡作用。本实验对这一假设进行了验证。
我们应用Western Blot检测心肌细胞缺氧损伤后HSP90蛋白表达规律,并运用GA抑制HSP90后检测缺氧状态下心肌细胞PI3K/Akt通路中的多种效应分子如Akt, Bcl-2家族促凋亡基因Bad,GSK-3β,细胞色素C等的蛋白表达变化。结果显示:心肌细胞中HSP90蛋白和磷酸化Akt在缺氧后表达明显增高,Akt下游效应分子Bad和GSK-3β的磷酸化水平升高,说明PI3K/Akt信号通路在心肌细胞缺氧早期也被激活。用GA抑制HSP90活性后Akt和Bad的磷酸化被阻断,从线粒体释放至细胞浆的细胞色素C明显增加,说明HSP90的心肌保护作用与PI3K/Akt信号通路相关,即HSP90保持Akt的磷酸化稳定性并促进Akt下游底物Bad的磷酸化,抑制细胞色素C从心肌细胞线粒体的释放,从而起到抗凋亡的作用。
另一方面,我们检测HSP90是否具有抗β肾上腺素能受体过度激活诱导的心肌细胞死亡的作用。我们利用异丙肾上腺素(Isoproterenol, ISO)诱导体外培养的成年小鼠心肌细胞死亡,模拟严重烧伤后β肾上腺素能受体持续激活诱导心肌细胞死亡。结果显示ISO对心肌细胞具有明显的细胞毒作用(导致心肌细胞坏死);用GA抑制HSP90后,ISO对心肌细胞的细胞毒作用不受影响,提示HSP90对GA对β肾上腺素能受体过度激活导致的心肌损伤无保护作用。
我们进一步探讨了β肾上腺素能受体过度激活导致心肌细胞死亡的作用机制,并寻求针对该损伤因素的心肌保护方法。研究发现严重烧伤发生后心肌细胞中出现大量的游离钙累积(钙超载),而且烧伤后通过细胞膜L型钙通道(LTCC)进入胞内的钙内流明显增加。因为LTCC是β肾上腺素能受体信号系统的重要底物蛋白,本实验假设:β肾上腺素能受体过度激活是通过增加经LTCC的钙内流导致心肌细胞坏死。因为LTCC和β肾上腺素能受体相互作用密切,以往的研究没有将二者有效分离开来研究其分别机制。本实验利用LTCC亚基β2a转基因小鼠模型首次检测了β肾上腺素能受体和LTCC在心肌细胞死亡中各自独立的作用机制。
我们原代分离成年野生型和转基因小鼠的心室肌细胞后进行体外培养,然后检测各种药物干预情况下(包括β肾上腺素能受体非选择性激动剂ISO、其他β肾上腺素能受体调节药物、钙调节蛋白的调控药物、caspase和活性氧簇抑制剂等)心肌细胞的生存率。同时我们还观察了β肾上腺素能受体各亚型的不同作用机制。
我们的结果发现:转基因心肌细胞在培养中的细胞死亡率明显高于野生型心肌细胞。野生型和转基因心肌细胞的死亡率都被ISO加重,但是ISO不增加转基因心肌细胞的LTCC大小,LTCC抑制剂Nifedipine只能部分抑制心肌细胞死亡。这些结果表明ISO诱导的心肌细胞死亡具有LTCC依赖和非依赖的两种机制。ISO通过增强肌浆网Ca2+ ATP酶(钙泵,SERCA),钠/钙交换蛋白(NCX)和钙/钙调蛋白依赖性激酶Ⅱ(CaMK II)的功能增加野生型和转基因心肌细胞的收缩功能。Caspase和ROS抑制剂不能减少LTCC或ISO导致的心肌细胞死亡。激活β2肾上腺素能受体具有一定的心肌保护作用。这些结果提示β肾上腺素能受体持续激活导致的心肌细胞坏死主要是通过β1肾上腺素能受体介导的LTCC增加的机制,但其他的机制参与不能排除。
总之,我们的研究提示HSP90具有抗缺氧诱导的凋亡的心肌保护作用。我们的研究还提示:通过减少通过LTCC的过度Ca2+内流、减少β1肾上腺素受体的激活,同时增加β2肾上腺素受体的激活新型联合治疗,可以减少各种病理应激所致的心肌细胞死亡。
Hypoxia-induced cardiomyocyte apoptosis contributes significantly to cardiac dysfunction following trauma, shock and burn injury. There is evidence that heat shock protein (HSP) 90 is anti-apoptotic in cardiomyocytes subjected to a variety of apoptotic stimuli. Because HSP90 acts as an upstream regulator of the serine/threonine protein kinase Akt survival pathway during cellular stress, we hypothesized that HSP90 exerts a cardioprotetive effect via the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Neonatal rat cardiomyocytes were subjected to normoxia or hypoxia in the absence or presence of the HSP90 inhibitor geldanamycin (GA, 1μg/ml). Cardiomyocyte apoptosis was assessed by release of lactate dehydrogenase (LDH), terminal deoxyribonucleotidyl transferase-mediated dUTP–digoxigenin nick end-labelling (TUNEL) staining and caspase 3 activity. Expression of HSP90, Akt, Bad and cytochrome c release was determined by western blot analysis.
Following exposure of cells to hypoxia, HSP90 was markedly elevated in a time-dependent manner, reaching a peak at 6 h (eightfold increase). Geldanamycin significantly increased hypoxia-induced release of LDH by 114%, the percentage of apoptotic cardiomyocytes by 102% and caspase 3 activity by 78%. Pretreatment of cells with geldanamycin also suppressed phosphorylation of both Akt and its downstream target Bad, but promoted the mitochondrial release of cytochrome c.
Adult mouse cardiomyocytes were subjected to isoproterenol (ISO, 0.1μmol/ml) in the absence or presence of the HSP90 inhibitor GA. GA neither affected the myocyte viability nor enhanced the ISO induced myocyte death.
In conclusion, HSP90 activity is enhanced in cardiomyocytes following hypoxic insult. The anti-apoptotic effect of HSP90 on cardiomyocytes subjected to hypoxia is mediated, at least in part, by the PI3K/Akt pathway. The cardioprotective effect of HSP90 is not mediated via attenuating the activation of adrenergic signaling pathways.
Cardiac diseases persistently increase the contractility demands of cardiac myocytes which met by activating the sympathetic nervous system and subsequently increasing myocyte Ca2+ transients. Persistent exposure to sympathetic and/or Ca2+ stress is associated with myocyte death. This study examined the respective roles of persistentβ-adrenergic receptor (β-AR) agonist exposure and high [Ca2+]i in myocyte death. Methods: Ventricular myocytes (VMs) were isolated from transgenic (TG) mice with cardiac specific and inducible expression of theβ2a subunit of the L-type Ca2+ channel (LTCC). VMs were cultured and the rate of myocyte death was measured in the presence of isoproterenol (ISO), other modulators of Ca2+ handling and theβ-adrenergic system, and inhibitors of caspases and reactive oxygen species (ROS) generation.
Results and Conclusions: The rate of myocyte death was greater in TG versus WT myocytes and accelerated by ISO in both groups although ISO did not increase LTCC current (ICa-L) in TG-VMs. Nifedipine, an LTCC antagonist, only partially prevented myocyte death. These results suggest both LTCC-dependent and independent mechanisms in ISO induced myocyte death. ISO increased the contractility of WT and TG-VMs by enhancing SR function and inhibiting SERCA, Na+/Ca2+ exchanger, and CaMK II partially protected myocyte from death induced by both Ca2+ and ISO. Caspase and ROS inhibitors did not butβ2-AR activation did reduce myocyte death induced by enhanced ICa-L and ISO stimulation. Our results suggest that catecholamines induce myocyte necrosis primarily throughβ1-AR mediated increases in ICa-L but other mechanisms are also involved in rodents.
热休克蛋白90 (HSP 90)作为一种分子伴侣,其作用是维护大量蛋白折叠和构象成熟。HSP90除了具有分子伴侣功能,还参与调节了多种细胞信号通路和细胞功能[3]。研究证明HSP90对多种凋亡诱导因子引起的心肌细胞凋亡具有保护作用。本实验首先检测了HSP90是否具有抗缺氧诱导的心肌细胞凋亡的作用。
我们建立体外培养的新生大鼠心肌细胞缺氧模型,应用HSP90的特异性抑制剂格尔德霉素(geldanamycin,GA)抑制心肌细胞HSP90活性。我们运用MTT法检测心肌细胞活力,酶联免疫(ELISA)试剂盒检测心肌细胞培养液中乳酸脱氢酶(LDH)的漏出率、TUNEL染色检测心肌凋亡率等观测多项细胞生物学指标。结果显示:缺氧引起心肌细胞膜结构破坏、细胞活力下降,并最终导致细胞凋亡;用GA抑制HSP90活性后,心肌细胞活力下降和细胞凋亡明显加剧。这些结果明确了HSP90对心肌具有抗缺氧损伤的内源性保护效应。
我们进一步探讨了HSP90抗缺氧诱导的心肌细胞凋亡的作用机制。磷脂酰肌醇3激酶/蛋白质丝氨酸苏氨酸激酶(PI3K/Akt)信号通路作为细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,在细胞内发挥着抑制凋亡、促进增殖的关键作用。PI3K/Akt信号通路能够提高心肌功能和促进心肌细胞的存活。研究提示HSP90可能是蛋白质丝氨酸/苏氨酸激酶(Akt)的上游调节分子。所以我们假设HSP90对严重烧伤后的心肌细胞的保护作用机制是通过调控PI3K/Akt通路的抗凋亡作用。本实验对这一假设进行了验证。
我们应用Western Blot检测心肌细胞缺氧损伤后HSP90蛋白表达规律,并运用GA抑制HSP90后检测缺氧状态下心肌细胞PI3K/Akt通路中的多种效应分子如Akt, Bcl-2家族促凋亡基因Bad,GSK-3β,细胞色素C等的蛋白表达变化。结果显示:心肌细胞中HSP90蛋白和磷酸化Akt在缺氧后表达明显增高,Akt下游效应分子Bad和GSK-3β的磷酸化水平升高,说明PI3K/Akt信号通路在心肌细胞缺氧早期也被激活。用GA抑制HSP90活性后Akt和Bad的磷酸化被阻断,从线粒体释放至细胞浆的细胞色素C明显增加,说明HSP90的心肌保护作用与PI3K/Akt信号通路相关,即HSP90保持Akt的磷酸化稳定性并促进Akt下游底物Bad的磷酸化,抑制细胞色素C从心肌细胞线粒体的释放,从而起到抗凋亡的作用。
另一方面,我们检测HSP90是否具有抗β肾上腺素能受体过度激活诱导的心肌细胞死亡的作用。我们利用异丙肾上腺素(Isoproterenol, ISO)诱导体外培养的成年小鼠心肌细胞死亡,模拟严重烧伤后β肾上腺素能受体持续激活诱导心肌细胞死亡。结果显示ISO对心肌细胞具有明显的细胞毒作用(导致心肌细胞坏死);用GA抑制HSP90后,ISO对心肌细胞的细胞毒作用不受影响,提示HSP90对GA对β肾上腺素能受体过度激活导致的心肌损伤无保护作用。
我们进一步探讨了β肾上腺素能受体过度激活导致心肌细胞死亡的作用机制,并寻求针对该损伤因素的心肌保护方法。研究发现严重烧伤发生后心肌细胞中出现大量的游离钙累积(钙超载),而且烧伤后通过细胞膜L型钙通道(LTCC)进入胞内的钙内流明显增加。因为LTCC是β肾上腺素能受体信号系统的重要底物蛋白,本实验假设:β肾上腺素能受体过度激活是通过增加经LTCC的钙内流导致心肌细胞坏死。因为LTCC和β肾上腺素能受体相互作用密切,以往的研究没有将二者有效分离开来研究其分别机制。本实验利用LTCC亚基β2a转基因小鼠模型首次检测了β肾上腺素能受体和LTCC在心肌细胞死亡中各自独立的作用机制。
我们原代分离成年野生型和转基因小鼠的心室肌细胞后进行体外培养,然后检测各种药物干预情况下(包括β肾上腺素能受体非选择性激动剂ISO、其他β肾上腺素能受体调节药物、钙调节蛋白的调控药物、caspase和活性氧簇抑制剂等)心肌细胞的生存率。同时我们还观察了β肾上腺素能受体各亚型的不同作用机制。
我们的结果发现:转基因心肌细胞在培养中的细胞死亡率明显高于野生型心肌细胞。野生型和转基因心肌细胞的死亡率都被ISO加重,但是ISO不增加转基因心肌细胞的LTCC大小,LTCC抑制剂Nifedipine只能部分抑制心肌细胞死亡。这些结果表明ISO诱导的心肌细胞死亡具有LTCC依赖和非依赖的两种机制。ISO通过增强肌浆网Ca2+ ATP酶(钙泵,SERCA),钠/钙交换蛋白(NCX)和钙/钙调蛋白依赖性激酶Ⅱ(CaMK II)的功能增加野生型和转基因心肌细胞的收缩功能。Caspase和ROS抑制剂不能减少LTCC或ISO导致的心肌细胞死亡。激活β2肾上腺素能受体具有一定的心肌保护作用。这些结果提示β肾上腺素能受体持续激活导致的心肌细胞坏死主要是通过β1肾上腺素能受体介导的LTCC增加的机制,但其他的机制参与不能排除。
总之,我们的研究提示HSP90具有抗缺氧诱导的凋亡的心肌保护作用。我们的研究还提示:通过减少通过LTCC的过度Ca2+内流、减少β1肾上腺素受体的激活,同时增加β2肾上腺素受体的激活新型联合治疗,可以减少各种病理应激所致的心肌细胞死亡。
Hypoxia-induced cardiomyocyte apoptosis contributes significantly to cardiac dysfunction following trauma, shock and burn injury. There is evidence that heat shock protein (HSP) 90 is anti-apoptotic in cardiomyocytes subjected to a variety of apoptotic stimuli. Because HSP90 acts as an upstream regulator of the serine/threonine protein kinase Akt survival pathway during cellular stress, we hypothesized that HSP90 exerts a cardioprotetive effect via the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Neonatal rat cardiomyocytes were subjected to normoxia or hypoxia in the absence or presence of the HSP90 inhibitor geldanamycin (GA, 1μg/ml). Cardiomyocyte apoptosis was assessed by release of lactate dehydrogenase (LDH), terminal deoxyribonucleotidyl transferase-mediated dUTP–digoxigenin nick end-labelling (TUNEL) staining and caspase 3 activity. Expression of HSP90, Akt, Bad and cytochrome c release was determined by western blot analysis.
Following exposure of cells to hypoxia, HSP90 was markedly elevated in a time-dependent manner, reaching a peak at 6 h (eightfold increase). Geldanamycin significantly increased hypoxia-induced release of LDH by 114%, the percentage of apoptotic cardiomyocytes by 102% and caspase 3 activity by 78%. Pretreatment of cells with geldanamycin also suppressed phosphorylation of both Akt and its downstream target Bad, but promoted the mitochondrial release of cytochrome c.
Adult mouse cardiomyocytes were subjected to isoproterenol (ISO, 0.1μmol/ml) in the absence or presence of the HSP90 inhibitor GA. GA neither affected the myocyte viability nor enhanced the ISO induced myocyte death.
In conclusion, HSP90 activity is enhanced in cardiomyocytes following hypoxic insult. The anti-apoptotic effect of HSP90 on cardiomyocytes subjected to hypoxia is mediated, at least in part, by the PI3K/Akt pathway. The cardioprotective effect of HSP90 is not mediated via attenuating the activation of adrenergic signaling pathways.
Cardiac diseases persistently increase the contractility demands of cardiac myocytes which met by activating the sympathetic nervous system and subsequently increasing myocyte Ca2+ transients. Persistent exposure to sympathetic and/or Ca2+ stress is associated with myocyte death. This study examined the respective roles of persistentβ-adrenergic receptor (β-AR) agonist exposure and high [Ca2+]i in myocyte death. Methods: Ventricular myocytes (VMs) were isolated from transgenic (TG) mice with cardiac specific and inducible expression of theβ2a subunit of the L-type Ca2+ channel (LTCC). VMs were cultured and the rate of myocyte death was measured in the presence of isoproterenol (ISO), other modulators of Ca2+ handling and theβ-adrenergic system, and inhibitors of caspases and reactive oxygen species (ROS) generation.
Results and Conclusions: The rate of myocyte death was greater in TG versus WT myocytes and accelerated by ISO in both groups although ISO did not increase LTCC current (ICa-L) in TG-VMs. Nifedipine, an LTCC antagonist, only partially prevented myocyte death. These results suggest both LTCC-dependent and independent mechanisms in ISO induced myocyte death. ISO increased the contractility of WT and TG-VMs by enhancing SR function and inhibiting SERCA, Na+/Ca2+ exchanger, and CaMK II partially protected myocyte from death induced by both Ca2+ and ISO. Caspase and ROS inhibitors did not butβ2-AR activation did reduce myocyte death induced by enhanced ICa-L and ISO stimulation. Our results suggest that catecholamines induce myocyte necrosis primarily throughβ1-AR mediated increases in ICa-L but other mechanisms are also involved in rodents.
引文
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