羟基红花黄素A对缺氧/复氧诱导的H9c2心肌细胞凋亡的影响及机制研究
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摘要
研究背景：
随着心脏移植、冠状动脉搭桥以及经皮冠脉介入等治疗手段广泛地应用于临床,心肌缺血再灌注损伤已成为临床上常见的一种病理生理现象。细胞凋亡在心肌缺血后即触发并因再灌注而加重,减少缺血和再灌注过程中心肌细胞凋亡可以挽救更多的心肌,提高心肌缺血后再灌注治疗的效果。
血红素氧合酶1(HO-1),是血红素氧合酶的诱导型,研究表明HO-1被诱导适应性表达能发挥抗细胞凋亡的作用。多种因素可通过信号转导通路ERK1/2或PI3K/Akt激活并促使红细胞系核因子-2相关因子-2(Nrf2)向核内转位、并与细胞核内抗氧化反应元件(ARE)上相应位点相互作用,上调HO-1的表达与酶活力,减轻各种应激状态下组织细胞的损伤。
羟基红花黄素A (HSYA)是药用植物红花的最主要的有效成分。研究发现,HSYA可以减轻组织细胞的缺血再灌注损伤,可以抑制低氧诱导的内皮细胞凋亡目前尚未见到有关HSYA对缺血再灌注过程中心肌细胞凋亡的影响及其机制的研究报道。本研究探讨HSYA对缺氧/复氧诱导的H9c2心肌细胞凋亡的影响及其分子机制,分两部分进行。
第一部分羟基红花黄素A上调血红素氧合酶-1的表达抑制缺氧／复氧诱导的H9c2心肌细胞凋亡
目的：
利用体外细胞缺氧/复氧(A/R)模拟体内组织细胞缺血再灌注诱导H9c2心肌细胞凋亡,给予HSYA干预,探讨其对A/R诱导的心肌细胞凋亡的影响和其分子机制。
方法：
H9c2心肌细胞随机分为对照组、A/R组、A/R并给予不同剂量(1、5、20、80μM) HSYA干预组,MTT法检测各组H9c2心肌细胞活力,酶联免疫分析法检测各组H9c2心肌细胞上清液肌钙蛋白Ⅰ浓度,蛋白免疫印迹技术测定各组H9c2心肌细胞HO-1蛋白表量。然后用随机分成的对照组、A/R组、A/R并给予HSYA20μM干预组、HO-1抑制剂(ZnPP-Ⅸ)组继续进一步的实验,测定各组H9c2心肌细胞的HO-1酶活力,FITC-Annexin V/PI双染流式细胞术检测各组H9c2心肌细胞的凋亡率,蛋白免疫印迹技术测定各组H9c2心肌细胞HO-1蛋白表量、裂解的caspase-3 (CC3)表达量和细胞线粒体Bcl-2/Bax比值。
结果：
1.HSYA提高了经历A/R的H9c2心肌细胞的活力。
2. HSYA减轻了经历A/R的H9c2心肌细胞的损伤。
3. HSYA上调了经历A/R的H9c2心肌细胞的HO-1表达。
4. ZnPP-Ⅸ对HSYA上调经历A/R的H9c2心肌细胞的HO-1表达的作用没有明显影响。
5. HSYA上调经历A/R的H9c2心肌细胞HO-1的酶活力被ZnPP-Ⅸ抑制。
6. HSYA抗A/R诱导H9c2心肌细胞凋亡的作用被ZnPP-Ⅸ部分消除。
7. ZnPP-Ⅸ部分地消除了HSYA上调经历A/R的H9c2心肌细胞线粒体Bcl-2/Bax比值的作用。
8. ZnPP-Ⅸ部分地消除了HSYA降低经历A/R的H9c2心肌细胞CC3表达量的作用。
结论：
HSYA通过上调HO-1的表达量和酶活力抑制A/R诱导的H9c2心心肌细胞凋亡从而减轻了细胞损伤。
第二部分羟基红花黄素A上调经历缺氧/复氧的H9c2心肌细胞血红素氧合酶-1的表达的信号转导通路
目的：
紧接着第一部分的研究工作,利用体外A/R模拟体内缺血再灌注诱导H9c2心肌细胞凋亡,并给予HSYA干预,探讨HSYA在抗A/R诱导的心肌细胞凋亡作用中上调HO-1表达的细胞信号转导通路机制。
方法：
H9c2心肌细胞随机分为对照组、A/R组、HSYA 20μM干预组、HO-1抑制剂组,蛋白免疫印迹技术测定各组H9c2心肌细胞p-ERK1/2, p-Akt蛋白表量。然后用随机分成的对照组、A/R组、HSYA 20μM干预组、P13K抑制剂(LY294002)组继续进一步的实验,蛋白免疫印迹技术测定各组H9c2心肌细胞p-Akt、HO-1、CC3蛋白表量和各组H9c2心肌细胞核蛋白中Nrf2的量。
结果：
1. HSYA和ZnPP-IX对经历A/R的H9c2心肌细胞的ERK1/2的磷酸化没有明显影响。
2. HSYA促进经历A/R的H9c2心肌细胞Akt磷酸化而ZnPP-Ⅸ对HSYA增强H9c2心肌细胞Akt磷酸化的作用没有明显影响。
3. HSYA促进经历A/R的H9c2心肌细胞Akt磷酸化的作用被LY294002阻断。
4.LY294002部分地阻断了HSYA上调经历A/R的H9c2心肌细胞HO-1表达的作用,并显著地削弱了HSYA降低经历A/R的H9c2心肌细胞CC3表达量的作用。
5. HSYA促进经历A/R的H9c2心肌细胞Nrf2向核内转位的作用被LY294002部分阻断。
结论：
HSYA减轻细胞损伤可能机制之一是通过激活PI3K/Akt信号转导通路,促使核因子Nrf2转位于细胞核内,与抗氧化反应元件上相应位点相互作用,从而上调血红素氧合酶1的表达和活性。
Background:
Since heart transplantation、coronary artery bypass grafting and percutaneous coronary intervention are widely utilized, acute ischemia-reperfusion (I/R) injury of the heart is a frequently encountered pathophysiology phenomenon in clinical practice. Apoptosis is initiated shortly after the onset of myocardial ischemia and becomes markedly enhanced during reperfusion. Thus, inhibiting the cardiomyocyte apoptosis induced by I/R will result in keeping more myocardium and improving reperfusion therapeutic effectiveness of acute myocardial ischemia.
Heme oxygenase-1 (HO-1) is the induction type of heme oxygenase, it was reported that could be induced to be overexpressed to anti-apoptosis.Many kinds of agents can upregulate HO-1 expression through activation of signaling pathways such as ERK1/2 and Akt, enhancing translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) to the nucleus, where it binds to antioxidant response element (ARE) sequences, leading to the transcriptional activation of HO-1 to provide protection to the cells against various forms of stress.
Hydroxysafflor yellow A (HSYA) is the overriding effective chemical component isolated from the flower of the medicinal plants safflower. Previous studies reported that HSYA can alleviate I/R injury and inhibite hypoxia-induced apoptosis of endothelial cells. However, there is still no report on the effect of HSYA on cardiomyocyte apoptosis induced by I/R, and the mechanisms of its effect are unclear. This study includes two experimental parts to investigate the effect and mechanisms of HSYA on A/R-induced apoptosis of the H9c2 cardiomyocytes.
Part 1:Upregulation of heme oxygenase-1 expression by hydroxysafflor yellow A inhibiting apoptosis induced by anoxia/reoxygenation of H9c2 cardiomyocytes
Objective:
We utilized the H9c2 cardiomyocytes subjected to anoxia-reoxygenation (A/R) in a serum-free medium in vitro simulating ischemia/reperfusion in vivo, which were treated by HSYA, to study the effect and mechanisms of HSYA on A/R-induced apoptosis of H9c2 cardiomyocytes.
Methods:
The cultured H9c2 cardiomyocytes were randomly divided into control (Con) groups. A/R groups, different dosage (1.5.20.80μM) HSYA treated groups, cell viability was measured by MTT, determination of cardiac troponin I concentrations in the supernatant was executed by enzyme linked immuno assay and Western blot analysis was used to measure the expression of HO-1 in the H9c2 cardiomyocytes of different groups. Then the H9c2 cardiomyocytes were randomly divided into Con groups. A/R groups,20μM HSYA treated groups and HO-1 inhibiter (ZnPP-Ⅸ) groups, which were gone ahead with additional experiment. Assay for HO-1 enzyme activity was executed, flow cytometric detection of apoptosis rate was used and Western blot analysis was used to measure the expression of HO-1、CC3 in H9c2 cardiomyocytes and the Bcl-2/Bax ratio in the mitochondria of the H9c2 cardiomyocytes of different groups.
results:
1. HSYA enhanced cell viability of the H9c2 cardiomyocytes subjected to A/R.
2. HSYA alleviated A/R injury of the H9c2 cardiomyocytes subjected to A/R.
3. HSYA upregulated HO-1 expresssion in the H9c2 cardiomyocytes subjected to A/R.
4. ZnPP-Ⅸhad no noticeable influence on HO-1 expression upregulated by HSYA in the H9c2 cardiomyocytes subjected to A/R.
5. HO-1 enzymatic activity upregulated by HSYA in the H9c2 cardiomyocytes subjected to A/R was completely suppressed by ZnPP-Ⅸ.
6. The effect of HSYA providing protection to the H9c2 cardiomyocytes against apoptosis induced by A/R was notably negated by ZnPP-Ⅸ.
7. The effect of HSYA increased the Bcl-2/Bax ratio in the mitochondria of the H9c2 cardiomyocytes subjected to A/R was partly negated by ZnPP-Ⅸ.
8. The effect of HSYA reduced caspase-3 activation of the H9c2 cardiomyocytes subjected to A/R was negated notably by ZnPP-Ⅸ.
Conclusions:
HSYA can provide protection to the H9c2 cardiomyocytes against apoptosis induced by A/R, and its antiapoptotic effect depends on the upregulation expression and enzymatic activity of HO-1.
Part 2:The signal transduction pathway of HSYA upregulating HO-1 expression in the H9c2 cardiomyocytes subjected to A/R
Objective:
Close behind the first experimental part, We utilized the H9c2 cardiomyocytes subjected to A/R in a serum-free medium in vitro simulating I/R in vivo, which were treated by HSYA, to study the signal transduction pathway of HSYA upregulating HO-1 expression in the H9c2 cardiomyocytes subjected to A/R.
Methods:
The cultured H9c2 cardiomyocytes were randomly divided into Con groups、A/R groups、HSYA(20μM) treated groups and HO-1 inhibiter groups, Western blot analysis was used to measure the expression of p-ERK1/2、p-Akt in the H9c2 cardiomyocytes of different groups. Then the H9c2 cardiomyocytes were randomly divided into Con groups、A/R groups、HSYA (20μM) treated groups and PI3K inhibiter (LY294002) groups, which were gone ahead with additional experiment. Western blot analysis was used to measure the expression of p-Akt、HO-1、CC3 in the H9c2 cardiomyocytes and Nrf2 levels in the nucleus of the H9c2 cardiomyocytes of different groups.
results:
1. HSYA or ZnPP-Ⅸhad no striking influence on ERK1/2 phosphorylation in the H9c2 cardiomyocytes subjected to A/R.
2. HSYA activated Akt phosphorylation in the H9c2 cardiomyocytes subjected to A/R, and ZnPP-Ⅸhad no influence on Akt phosphorylation activated by HSYA.
3. Akt phosphorylation activated by HSYA in the H9c2 cardiomyocytes subjected to A/R was completely blocked by LY294002.
4.The CC3 levels supressed by HSYA in the H9c2 cardiomyocytes subjected to A/R was notably negated by LY294002, and HO-1 expression upregulated by HSYA in the H9c2 cardiomyocytes subjected to A/R was partly blocked by LY294002.
5. HSYA enhanced the translocation of Nrf2 to the nucleus in the H9c2 cardiomyocytes subjected to A/R, which was partly blocked by LY294002.
Conclusions:
HSYA can provide protection to the H9c2 cardiomyocytes against apoptosis induced by A/R. Its antiapoptotic effect largely depends on the upregulation expression and enzymatic activity of HO-1 via the PI3K/Akt pathway, enhancing the translocation of Nrf2 to the nucleus and binding to ARE sequences, leading to the transcriptional activation of HO-1.
随着心脏移植、冠状动脉搭桥以及经皮冠脉介入等治疗手段广泛地应用于临床,心肌缺血再灌注损伤已成为临床上常见的一种病理生理现象。细胞凋亡在心肌缺血后即触发并因再灌注而加重,减少缺血和再灌注过程中心肌细胞凋亡可以挽救更多的心肌,提高心肌缺血后再灌注治疗的效果。
血红素氧合酶1(HO-1),是血红素氧合酶的诱导型,研究表明HO-1被诱导适应性表达能发挥抗细胞凋亡的作用。多种因素可通过信号转导通路ERK1/2或PI3K/Akt激活并促使红细胞系核因子-2相关因子-2(Nrf2)向核内转位、并与细胞核内抗氧化反应元件(ARE)上相应位点相互作用,上调HO-1的表达与酶活力,减轻各种应激状态下组织细胞的损伤。
羟基红花黄素A (HSYA)是药用植物红花的最主要的有效成分。研究发现,HSYA可以减轻组织细胞的缺血再灌注损伤,可以抑制低氧诱导的内皮细胞凋亡目前尚未见到有关HSYA对缺血再灌注过程中心肌细胞凋亡的影响及其机制的研究报道。本研究探讨HSYA对缺氧/复氧诱导的H9c2心肌细胞凋亡的影响及其分子机制,分两部分进行。
第一部分羟基红花黄素A上调血红素氧合酶-1的表达抑制缺氧／复氧诱导的H9c2心肌细胞凋亡
目的：
利用体外细胞缺氧/复氧(A/R)模拟体内组织细胞缺血再灌注诱导H9c2心肌细胞凋亡,给予HSYA干预,探讨其对A/R诱导的心肌细胞凋亡的影响和其分子机制。
方法：
H9c2心肌细胞随机分为对照组、A/R组、A/R并给予不同剂量(1、5、20、80μM) HSYA干预组,MTT法检测各组H9c2心肌细胞活力,酶联免疫分析法检测各组H9c2心肌细胞上清液肌钙蛋白Ⅰ浓度,蛋白免疫印迹技术测定各组H9c2心肌细胞HO-1蛋白表量。然后用随机分成的对照组、A/R组、A/R并给予HSYA20μM干预组、HO-1抑制剂(ZnPP-Ⅸ)组继续进一步的实验,测定各组H9c2心肌细胞的HO-1酶活力,FITC-Annexin V/PI双染流式细胞术检测各组H9c2心肌细胞的凋亡率,蛋白免疫印迹技术测定各组H9c2心肌细胞HO-1蛋白表量、裂解的caspase-3 (CC3)表达量和细胞线粒体Bcl-2/Bax比值。
结果：
1.HSYA提高了经历A/R的H9c2心肌细胞的活力。
2. HSYA减轻了经历A/R的H9c2心肌细胞的损伤。
3. HSYA上调了经历A/R的H9c2心肌细胞的HO-1表达。
4. ZnPP-Ⅸ对HSYA上调经历A/R的H9c2心肌细胞的HO-1表达的作用没有明显影响。
5. HSYA上调经历A/R的H9c2心肌细胞HO-1的酶活力被ZnPP-Ⅸ抑制。
6. HSYA抗A/R诱导H9c2心肌细胞凋亡的作用被ZnPP-Ⅸ部分消除。
7. ZnPP-Ⅸ部分地消除了HSYA上调经历A/R的H9c2心肌细胞线粒体Bcl-2/Bax比值的作用。
8. ZnPP-Ⅸ部分地消除了HSYA降低经历A/R的H9c2心肌细胞CC3表达量的作用。
结论：
HSYA通过上调HO-1的表达量和酶活力抑制A/R诱导的H9c2心心肌细胞凋亡从而减轻了细胞损伤。
第二部分羟基红花黄素A上调经历缺氧/复氧的H9c2心肌细胞血红素氧合酶-1的表达的信号转导通路
目的：
紧接着第一部分的研究工作,利用体外A/R模拟体内缺血再灌注诱导H9c2心肌细胞凋亡,并给予HSYA干预,探讨HSYA在抗A/R诱导的心肌细胞凋亡作用中上调HO-1表达的细胞信号转导通路机制。
方法：
H9c2心肌细胞随机分为对照组、A/R组、HSYA 20μM干预组、HO-1抑制剂组,蛋白免疫印迹技术测定各组H9c2心肌细胞p-ERK1/2, p-Akt蛋白表量。然后用随机分成的对照组、A/R组、HSYA 20μM干预组、P13K抑制剂(LY294002)组继续进一步的实验,蛋白免疫印迹技术测定各组H9c2心肌细胞p-Akt、HO-1、CC3蛋白表量和各组H9c2心肌细胞核蛋白中Nrf2的量。
结果：
1. HSYA和ZnPP-IX对经历A/R的H9c2心肌细胞的ERK1/2的磷酸化没有明显影响。
2. HSYA促进经历A/R的H9c2心肌细胞Akt磷酸化而ZnPP-Ⅸ对HSYA增强H9c2心肌细胞Akt磷酸化的作用没有明显影响。
3. HSYA促进经历A/R的H9c2心肌细胞Akt磷酸化的作用被LY294002阻断。
4.LY294002部分地阻断了HSYA上调经历A/R的H9c2心肌细胞HO-1表达的作用,并显著地削弱了HSYA降低经历A/R的H9c2心肌细胞CC3表达量的作用。
5. HSYA促进经历A/R的H9c2心肌细胞Nrf2向核内转位的作用被LY294002部分阻断。
结论：
HSYA减轻细胞损伤可能机制之一是通过激活PI3K/Akt信号转导通路,促使核因子Nrf2转位于细胞核内,与抗氧化反应元件上相应位点相互作用,从而上调血红素氧合酶1的表达和活性。
Background:
Since heart transplantation、coronary artery bypass grafting and percutaneous coronary intervention are widely utilized, acute ischemia-reperfusion (I/R) injury of the heart is a frequently encountered pathophysiology phenomenon in clinical practice. Apoptosis is initiated shortly after the onset of myocardial ischemia and becomes markedly enhanced during reperfusion. Thus, inhibiting the cardiomyocyte apoptosis induced by I/R will result in keeping more myocardium and improving reperfusion therapeutic effectiveness of acute myocardial ischemia.
Heme oxygenase-1 (HO-1) is the induction type of heme oxygenase, it was reported that could be induced to be overexpressed to anti-apoptosis.Many kinds of agents can upregulate HO-1 expression through activation of signaling pathways such as ERK1/2 and Akt, enhancing translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) to the nucleus, where it binds to antioxidant response element (ARE) sequences, leading to the transcriptional activation of HO-1 to provide protection to the cells against various forms of stress.
Hydroxysafflor yellow A (HSYA) is the overriding effective chemical component isolated from the flower of the medicinal plants safflower. Previous studies reported that HSYA can alleviate I/R injury and inhibite hypoxia-induced apoptosis of endothelial cells. However, there is still no report on the effect of HSYA on cardiomyocyte apoptosis induced by I/R, and the mechanisms of its effect are unclear. This study includes two experimental parts to investigate the effect and mechanisms of HSYA on A/R-induced apoptosis of the H9c2 cardiomyocytes.
Part 1:Upregulation of heme oxygenase-1 expression by hydroxysafflor yellow A inhibiting apoptosis induced by anoxia/reoxygenation of H9c2 cardiomyocytes
Objective:
We utilized the H9c2 cardiomyocytes subjected to anoxia-reoxygenation (A/R) in a serum-free medium in vitro simulating ischemia/reperfusion in vivo, which were treated by HSYA, to study the effect and mechanisms of HSYA on A/R-induced apoptosis of H9c2 cardiomyocytes.
Methods:
The cultured H9c2 cardiomyocytes were randomly divided into control (Con) groups. A/R groups, different dosage (1.5.20.80μM) HSYA treated groups, cell viability was measured by MTT, determination of cardiac troponin I concentrations in the supernatant was executed by enzyme linked immuno assay and Western blot analysis was used to measure the expression of HO-1 in the H9c2 cardiomyocytes of different groups. Then the H9c2 cardiomyocytes were randomly divided into Con groups. A/R groups,20μM HSYA treated groups and HO-1 inhibiter (ZnPP-Ⅸ) groups, which were gone ahead with additional experiment. Assay for HO-1 enzyme activity was executed, flow cytometric detection of apoptosis rate was used and Western blot analysis was used to measure the expression of HO-1、CC3 in H9c2 cardiomyocytes and the Bcl-2/Bax ratio in the mitochondria of the H9c2 cardiomyocytes of different groups.
results:
1. HSYA enhanced cell viability of the H9c2 cardiomyocytes subjected to A/R.
2. HSYA alleviated A/R injury of the H9c2 cardiomyocytes subjected to A/R.
3. HSYA upregulated HO-1 expresssion in the H9c2 cardiomyocytes subjected to A/R.
4. ZnPP-Ⅸhad no noticeable influence on HO-1 expression upregulated by HSYA in the H9c2 cardiomyocytes subjected to A/R.
5. HO-1 enzymatic activity upregulated by HSYA in the H9c2 cardiomyocytes subjected to A/R was completely suppressed by ZnPP-Ⅸ.
6. The effect of HSYA providing protection to the H9c2 cardiomyocytes against apoptosis induced by A/R was notably negated by ZnPP-Ⅸ.
7. The effect of HSYA increased the Bcl-2/Bax ratio in the mitochondria of the H9c2 cardiomyocytes subjected to A/R was partly negated by ZnPP-Ⅸ.
8. The effect of HSYA reduced caspase-3 activation of the H9c2 cardiomyocytes subjected to A/R was negated notably by ZnPP-Ⅸ.
Conclusions:
HSYA can provide protection to the H9c2 cardiomyocytes against apoptosis induced by A/R, and its antiapoptotic effect depends on the upregulation expression and enzymatic activity of HO-1.
Part 2:The signal transduction pathway of HSYA upregulating HO-1 expression in the H9c2 cardiomyocytes subjected to A/R
Objective:
Close behind the first experimental part, We utilized the H9c2 cardiomyocytes subjected to A/R in a serum-free medium in vitro simulating I/R in vivo, which were treated by HSYA, to study the signal transduction pathway of HSYA upregulating HO-1 expression in the H9c2 cardiomyocytes subjected to A/R.
Methods:
The cultured H9c2 cardiomyocytes were randomly divided into Con groups、A/R groups、HSYA(20μM) treated groups and HO-1 inhibiter groups, Western blot analysis was used to measure the expression of p-ERK1/2、p-Akt in the H9c2 cardiomyocytes of different groups. Then the H9c2 cardiomyocytes were randomly divided into Con groups、A/R groups、HSYA (20μM) treated groups and PI3K inhibiter (LY294002) groups, which were gone ahead with additional experiment. Western blot analysis was used to measure the expression of p-Akt、HO-1、CC3 in the H9c2 cardiomyocytes and Nrf2 levels in the nucleus of the H9c2 cardiomyocytes of different groups.
results:
1. HSYA or ZnPP-Ⅸhad no striking influence on ERK1/2 phosphorylation in the H9c2 cardiomyocytes subjected to A/R.
2. HSYA activated Akt phosphorylation in the H9c2 cardiomyocytes subjected to A/R, and ZnPP-Ⅸhad no influence on Akt phosphorylation activated by HSYA.
3. Akt phosphorylation activated by HSYA in the H9c2 cardiomyocytes subjected to A/R was completely blocked by LY294002.
4.The CC3 levels supressed by HSYA in the H9c2 cardiomyocytes subjected to A/R was notably negated by LY294002, and HO-1 expression upregulated by HSYA in the H9c2 cardiomyocytes subjected to A/R was partly blocked by LY294002.
5. HSYA enhanced the translocation of Nrf2 to the nucleus in the H9c2 cardiomyocytes subjected to A/R, which was partly blocked by LY294002.
Conclusions:
HSYA can provide protection to the H9c2 cardiomyocytes against apoptosis induced by A/R. Its antiapoptotic effect largely depends on the upregulation expression and enzymatic activity of HO-1 via the PI3K/Akt pathway, enhancing the translocation of Nrf2 to the nucleus and binding to ARE sequences, leading to the transcriptional activation of HO-1.
引文
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