蛋白O-乙酰葡糖胺糖基化在心肌细胞和内皮细胞的高糖损害中的作用
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摘要
糖尿病心血管损害是糖尿病并发症中最主要的致死和致残原因。其中糖尿病心肌病是来自于心肌细胞自身的损害,独立于冠状动脉粥样硬化性心脏病、高血压和其他心脏结构性变化而存在的心功能不全。心肌病变在糖尿病早期即可存在,并伴随糖尿病病程始终,晚期伴随的心力衰竭将大大降低病人的生活质量,并增加死亡率。糖尿病病人的动脉粥样硬化性病变,可导致多种缺血事件包括脑卒中、心肌梗死、下肢坏死等。闭塞性动脉病变部位的血管新生和侧枝循环形成可促进受累缺血组织和器官的修复和改善预后,而糖尿病却抑制了这种成血管能力。糖尿病心血管系统损害影响范围广泛,形式多样,可导致极为严重的后果,一直以来极为受到重视。对于其发病机制的研究一直以来都是热点。近年高糖及随后的氧化应激诱导的己糖胺通路激活和蛋白O-乙酰葡糖胺糖基化修饰吸引了研究者们的注意,越来越多证据支持这种蛋白转录后调控机制可直接和间接的调控了很多信号传导和病理生理过程。
本研究试图在既往研究的基础上,寻找高糖诱导的O-乙酰葡糖胺糖基化在糖尿病心血管病变,尤其在心肌细胞和血管内皮细胞中的作用,从而为糖尿病心肌病变和血管并发症找到新的视点和治疗靶点。
1.O-乙酰葡糖胺糖基化通过激活ERK1/2和上调cyclin D2介导高糖诱导的新生大鼠心肌细胞肥大
持续性高血糖是最重要的糖尿病心肌病的致病原因。糖尿病主要表现为心脏肥大及随后的心力衰竭。过去10几年O-乙酰葡糖胺糖基化作为一种蛋白转录后修饰受到关注,而其在高糖诱导的心肌细胞肥大过程中的作用还不明确。因此我们研究了高糖环境下培养新生大鼠心肌细胞内O-乙酰葡糖胺糖基化的作用。结果发现高糖(30mM)孵育72小时可导致心肌细胞增大2倍余,伴随肥大基因表达增加和O-乙酰葡糖胺糖基化水平升高。它同时激活ERK1/2,也上调cyclin D2表达,但不影响p38和JNK活性。乙酰葡糖胺糖苷酶PUGNac在增加细胞O-乙酰葡糖胺糖基化水平同时,模拟了高糖的上述效应。通过siRNA干扰O-乙酰葡糖胺转移酶来降低O-乙酰葡糖胺糖基化水平及以PD98059抑制ERK1/2激活均可降低心肌细胞肥大反应和cyclin D2上调。O-乙酰葡糖胺转移酶干扰也可阻止ERK1/2激活。以上结果揭示升高的O-乙酰葡糖胺糖基化水平通过激活ERK1/2和上调cyclin D2参与调控高糖诱导的心肌细胞肥大过程。
2.糖尿病大鼠早期病变心肌组织中O-乙酰葡糖胺糖基化水平、ERK1/2和cyclinD2的变化
我们发现高糖诱导的新生大鼠心肌细胞肥大过程中,O-乙酰葡糖胺糖基化通过激活ERK1/2和上调cyclin D2参与调控。为了证实这种调控作用的在体生理意义,我们用链脲佐霉素建立糖尿病大鼠模型,4周后即处死进行超声检测、病理切片及蛋白和mRNA检测,结果显示糖尿病组心室肌呈向心性肥大,心肌细胞有肥大性改变,心肌组织肥大基因mRNA表达增加,蛋白O-乙酰葡糖胺糖基化水平升高伴ERK1/2激活和cyclin D2表达上调,与心肌细胞实验结果一致,证实了O-乙酰葡糖胺糖基化通过激活ERK1/2和上调cyclin D2参与调控心肌肥大的机制参与糖尿病大鼠在体心肌病变进程。
3.O-乙酰葡糖胺糖基化在高糖抑制人脐静脉内皮细胞增殖迁移过程中的作用
既往体外和体内实验均证实高糖抑制了内皮细胞的成血管能力,而内皮细胞的增殖和迁移是成血管过程的基础。高糖诱导的O-乙酰葡糖胺糖基化水平升高在高糖诱导的内皮细胞损害中的作用仍在探索中。基于心肌细胞中O-乙酰葡糖胺糖基化的调控作用,我们研究了高糖环境下人脐静脉内皮细胞的增殖迁移受到的影响,及O-乙酰葡糖胺糖基化水平对其的调控作用。结果显示高糖抑制了内皮细胞的增殖和迁移,O-乙酰葡糖胺糖基化的增加和抑制可相应抑制和恢复内皮细胞的增殖和迁移,虽然ERK1/2和cyclin D2仍可被高糖上调,但并不能发挥其本应有的促有丝分裂作用。抑制ERK1/2及伴随的cyclin D2下调也没有调控作用,提示ERK1/2激活及随之上调的cyclin D2在血管内皮细胞的高糖效应中的作用被其他通路掩盖。
Diabetic cardiovascular disease is the most important cause of disabling and death in diabetic complications. Diabetic cardiomyopathy is defined as ventricular dysfunction occurring independently of a recognized cause, such as coronary artery disease or hypertension, which manifests as cardiac hypertrophy and subsequent heart failure. The lesion of myocardium occurs at the beginning and in the whole process of diabetes. The cardiac failure of end stage damages quality of life and increase mortality. Atherosclerosis in diabetes causes multiple ischemic events including stroke, myocardium infarction and lower extremity amputation. Angiogenesis and collateral vessel formation repair ischemic tissues and organs involved and improve prognosis. Diabetic complications of cardiovascular system act on wide range of organs and induced fatal consequences, therefore researchers kept enthusiasm on the mechanism of diabetic cardiovascular disease. Recent decade, increased hexosamine pathway and O-GlcNAcylation level induced by high glucose and subsequent oxidative stress attracted attention. The post-transcription modulation of proteins was shown mediated a seris of signaling transduction and physiology/pathology process. We aimed to disclose the role of O-GlcNAcylation induced by high glucose in diabetic cardiovascular disease, especially in cardiomyocytes and endothelial cells, and get a new sight and therapeutic target.
Part Ⅰ O-GlcNAcylation Involvement in High Glucose-Induced Cardiomyocyte Hypertrophy via ERK1/2and Cyclin D2
Continuous hyperglycemia is considered to be the most significant pathogenesis of diabetic cardiomyopathy, which manifests as cardiac hypertrophy and subsequent heart failure. O-GlcNAcylation has attracted attention as a post-translational protein modification in the past decade. The role of O-GlcNAcylation in high glucose-induced cardiomyocyte hypertrophy remains unclear. Therefore, we studied the effect of O-GlcNAcylation on neonatal rat cardiomyocytes (NRCMs) that were exposed to high glucose. High glucose (30mM) incubation for72hours induced a greater than2-fold increase in cell size and increased hypertrophy marker gene expression accompanied by elevated O-GlcNAcylation protein levels. High glucose increased ERK1/2but not p38MAPK or JNK activity, and cyclin D2expression was also increased. PUGNac, an inhibitor of β-N-acetylglucosaminidase, enhanced O-GlcNAcylation and imitated the effects of high glucose. OGT siRNA and ERK1/2inhibition with PD98059treatment blunted the hypertrophic response and cyclin D2upregulation. OGT inhibition also prevented ERK1/2activation. In conclusion, O-GlcNAcylation plays a role in high glucose-induced cardiac hypertrophy via ERK1/2and cyclin D2.
Part Ⅱ Modification O-GlcNAcylation, ERK1/2and cyclin D2in myocardium of diabetic rats in early stage
Rat model of diabetes was induced by injecting streptozocin to confirm the effect of O-GlcNAcylation in diabetic cardiomyopathy. Pathological observation and protein and mRNA analysis of the cardium tissue from diabetic rats4weeks later indicated concentric hypertrophy of heart, hypertrophic cardiomyocytes, upregulated hypertrophic genes, accompanied by elevated O-GlcNAcylation protein levels, activated ERK1/2and increased expression of cyclin D2. The results supported the conclusion from cell culture study.
Part Ⅲ O-GlcNAcylation Involvement in dysfunction of Human Umbilical Vein Endothelial Cells exposed to high glucose
High glucose inhibited angiogenesis in vivo and vitro which was based on proliferation and migration of endothelial cells. We observed proliferation and migration of human umbilical vein endothelial cells exposed to high glucose and effect of O-GlcNAcylation in the process. It was shown that high glucose inhibited the proliferation and migration, with was imitated by PUGNac and reverted by siRNA of OGT. Whereas activated ERK1/2and upregulated cyclin D2didn't play a major role in the effect of high glucose on endothelial cells. Therefore, O-GlcNAcylation regulated the high glucose induced-dysfunction of endothelial cells, and the effect of activate EKR1/2and upregulated cyclin D2was covered.
本研究试图在既往研究的基础上,寻找高糖诱导的O-乙酰葡糖胺糖基化在糖尿病心血管病变,尤其在心肌细胞和血管内皮细胞中的作用,从而为糖尿病心肌病变和血管并发症找到新的视点和治疗靶点。
1.O-乙酰葡糖胺糖基化通过激活ERK1/2和上调cyclin D2介导高糖诱导的新生大鼠心肌细胞肥大
持续性高血糖是最重要的糖尿病心肌病的致病原因。糖尿病主要表现为心脏肥大及随后的心力衰竭。过去10几年O-乙酰葡糖胺糖基化作为一种蛋白转录后修饰受到关注,而其在高糖诱导的心肌细胞肥大过程中的作用还不明确。因此我们研究了高糖环境下培养新生大鼠心肌细胞内O-乙酰葡糖胺糖基化的作用。结果发现高糖(30mM)孵育72小时可导致心肌细胞增大2倍余,伴随肥大基因表达增加和O-乙酰葡糖胺糖基化水平升高。它同时激活ERK1/2,也上调cyclin D2表达,但不影响p38和JNK活性。乙酰葡糖胺糖苷酶PUGNac在增加细胞O-乙酰葡糖胺糖基化水平同时,模拟了高糖的上述效应。通过siRNA干扰O-乙酰葡糖胺转移酶来降低O-乙酰葡糖胺糖基化水平及以PD98059抑制ERK1/2激活均可降低心肌细胞肥大反应和cyclin D2上调。O-乙酰葡糖胺转移酶干扰也可阻止ERK1/2激活。以上结果揭示升高的O-乙酰葡糖胺糖基化水平通过激活ERK1/2和上调cyclin D2参与调控高糖诱导的心肌细胞肥大过程。
2.糖尿病大鼠早期病变心肌组织中O-乙酰葡糖胺糖基化水平、ERK1/2和cyclinD2的变化
我们发现高糖诱导的新生大鼠心肌细胞肥大过程中,O-乙酰葡糖胺糖基化通过激活ERK1/2和上调cyclin D2参与调控。为了证实这种调控作用的在体生理意义,我们用链脲佐霉素建立糖尿病大鼠模型,4周后即处死进行超声检测、病理切片及蛋白和mRNA检测,结果显示糖尿病组心室肌呈向心性肥大,心肌细胞有肥大性改变,心肌组织肥大基因mRNA表达增加,蛋白O-乙酰葡糖胺糖基化水平升高伴ERK1/2激活和cyclin D2表达上调,与心肌细胞实验结果一致,证实了O-乙酰葡糖胺糖基化通过激活ERK1/2和上调cyclin D2参与调控心肌肥大的机制参与糖尿病大鼠在体心肌病变进程。
3.O-乙酰葡糖胺糖基化在高糖抑制人脐静脉内皮细胞增殖迁移过程中的作用
既往体外和体内实验均证实高糖抑制了内皮细胞的成血管能力,而内皮细胞的增殖和迁移是成血管过程的基础。高糖诱导的O-乙酰葡糖胺糖基化水平升高在高糖诱导的内皮细胞损害中的作用仍在探索中。基于心肌细胞中O-乙酰葡糖胺糖基化的调控作用,我们研究了高糖环境下人脐静脉内皮细胞的增殖迁移受到的影响,及O-乙酰葡糖胺糖基化水平对其的调控作用。结果显示高糖抑制了内皮细胞的增殖和迁移,O-乙酰葡糖胺糖基化的增加和抑制可相应抑制和恢复内皮细胞的增殖和迁移,虽然ERK1/2和cyclin D2仍可被高糖上调,但并不能发挥其本应有的促有丝分裂作用。抑制ERK1/2及伴随的cyclin D2下调也没有调控作用,提示ERK1/2激活及随之上调的cyclin D2在血管内皮细胞的高糖效应中的作用被其他通路掩盖。
Diabetic cardiovascular disease is the most important cause of disabling and death in diabetic complications. Diabetic cardiomyopathy is defined as ventricular dysfunction occurring independently of a recognized cause, such as coronary artery disease or hypertension, which manifests as cardiac hypertrophy and subsequent heart failure. The lesion of myocardium occurs at the beginning and in the whole process of diabetes. The cardiac failure of end stage damages quality of life and increase mortality. Atherosclerosis in diabetes causes multiple ischemic events including stroke, myocardium infarction and lower extremity amputation. Angiogenesis and collateral vessel formation repair ischemic tissues and organs involved and improve prognosis. Diabetic complications of cardiovascular system act on wide range of organs and induced fatal consequences, therefore researchers kept enthusiasm on the mechanism of diabetic cardiovascular disease. Recent decade, increased hexosamine pathway and O-GlcNAcylation level induced by high glucose and subsequent oxidative stress attracted attention. The post-transcription modulation of proteins was shown mediated a seris of signaling transduction and physiology/pathology process. We aimed to disclose the role of O-GlcNAcylation induced by high glucose in diabetic cardiovascular disease, especially in cardiomyocytes and endothelial cells, and get a new sight and therapeutic target.
Part Ⅰ O-GlcNAcylation Involvement in High Glucose-Induced Cardiomyocyte Hypertrophy via ERK1/2and Cyclin D2
Continuous hyperglycemia is considered to be the most significant pathogenesis of diabetic cardiomyopathy, which manifests as cardiac hypertrophy and subsequent heart failure. O-GlcNAcylation has attracted attention as a post-translational protein modification in the past decade. The role of O-GlcNAcylation in high glucose-induced cardiomyocyte hypertrophy remains unclear. Therefore, we studied the effect of O-GlcNAcylation on neonatal rat cardiomyocytes (NRCMs) that were exposed to high glucose. High glucose (30mM) incubation for72hours induced a greater than2-fold increase in cell size and increased hypertrophy marker gene expression accompanied by elevated O-GlcNAcylation protein levels. High glucose increased ERK1/2but not p38MAPK or JNK activity, and cyclin D2expression was also increased. PUGNac, an inhibitor of β-N-acetylglucosaminidase, enhanced O-GlcNAcylation and imitated the effects of high glucose. OGT siRNA and ERK1/2inhibition with PD98059treatment blunted the hypertrophic response and cyclin D2upregulation. OGT inhibition also prevented ERK1/2activation. In conclusion, O-GlcNAcylation plays a role in high glucose-induced cardiac hypertrophy via ERK1/2and cyclin D2.
Part Ⅱ Modification O-GlcNAcylation, ERK1/2and cyclin D2in myocardium of diabetic rats in early stage
Rat model of diabetes was induced by injecting streptozocin to confirm the effect of O-GlcNAcylation in diabetic cardiomyopathy. Pathological observation and protein and mRNA analysis of the cardium tissue from diabetic rats4weeks later indicated concentric hypertrophy of heart, hypertrophic cardiomyocytes, upregulated hypertrophic genes, accompanied by elevated O-GlcNAcylation protein levels, activated ERK1/2and increased expression of cyclin D2. The results supported the conclusion from cell culture study.
Part Ⅲ O-GlcNAcylation Involvement in dysfunction of Human Umbilical Vein Endothelial Cells exposed to high glucose
High glucose inhibited angiogenesis in vivo and vitro which was based on proliferation and migration of endothelial cells. We observed proliferation and migration of human umbilical vein endothelial cells exposed to high glucose and effect of O-GlcNAcylation in the process. It was shown that high glucose inhibited the proliferation and migration, with was imitated by PUGNac and reverted by siRNA of OGT. Whereas activated ERK1/2and upregulated cyclin D2didn't play a major role in the effect of high glucose on endothelial cells. Therefore, O-GlcNAcylation regulated the high glucose induced-dysfunction of endothelial cells, and the effect of activate EKR1/2and upregulated cyclin D2was covered.
引文
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