钙调神经磷酸酶信号通路在心肌肥厚和心衰发生机制中的研究
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摘要
研究背景:
心力衰竭是不同病因所致的心脏病发展的最终结局。目前对心力衰竭的防治虽取得了不少进展,但其患病率和死亡率仍居高不下,因而进一步加强心力衰竭的防治研究有着重大的意义。心肌肥厚是临床上发生心力衰竭的前期表现,是心肌为了满足不断增加的心脏做功需要而发生的代偿性变化,这种变化在短时间内可维持或增加心输出量。但心肌肥厚也会增加心肌耗氧量,降低冠状动脉血流储备,长期的供需失衡将会使“代偿性”肥厚逐渐发展为“失代偿性”肥厚,如果再同时合并心肌纤维化和细胞凋亡,最终将导致心功能下降而出现心衰的临床表现。因此,探讨心肌肥厚发生机制以及如何进展为心力衰竭非常重要,可能由此而发现新的心力衰竭防治措施。
心肌肥厚的病理变化包括基因转录和蛋白合成增加,以及肌原纤维重新组装,多数合并胚胎基因表达增加,包括利钠肽和胎儿收缩蛋白基因。利钠肽基因的出现是所有哺乳动物心肌肥厚的特征,也是临床上判断疾病严重程度的预测指标。迄今为止,已发现了许多可引起心肌肥厚的病理生理刺激因子,如机械应力、G-蛋白偶联受体(GPCR)激动剂(包括内皮素-1、人尿压素Ⅱ、血管紧张素-Ⅱ)、细胞因子和生长因子。这些刺激因子涉及到许多细胞内信号传导通路,包括丝裂原活化蛋白激酶(MAPK)、蛋白激酶C(PKC)、磷脂酰肌醇3-激酶(PI3-K)-Akt(又称蛋白激酶B)、Janus激酶-信号传导与转录活化因子(JAK-STAT)和白介素6-白介素6受体-糖蛋白130(IL6-IL6R-gp130)。近年来,钙调神经磷酸酶(Calcineurin)作为Ca~(2+)-介导造成心肌肥厚的重要调
Background: Heart failure is an important and growing public health problem and the cause of substantial morbidity and mortality. Hypertrophy is an early event in the clinical course of heart failure. In response to increased cardiac work demand, the heart increases muscle mass thereby providing temporary maintenance of cardiac output. In short term hypertrophy maintains or increases cardiac output. So it can be viewed as a "beneficial" compensatory response. However, hypertrophy also increases oxygen consumption and reduces coronary blood-flow reserve. This supply-demand mismatch may lead the patient to angina pectoris, MI, arrhythmia or sudden death. In addition, during the process of hypertrophy, cardiac fibrosis and apoptosis may occur simultaneously. All these co-existing pathologies mediate the eventual decline in myocardial function and lead to congestive heart failure. So, the investigation of mechanisms for cardiac hypertrophy and its progression to heart failure is very important, as this may lead to the development of new therapeutic modalities and better guidelines for the prevention of cardiac disease.Pathological changes resulting in cardiac hypertrophy include the increase of gene transcription, protein synthesis, and myofibril assembly. In most forms of cardiac hypertrophy, there is an increase in the expression of embryonic genes, including the genes of natriuretic peptides and fetal contractile proteins. The induction of the natriuretic peptide genes is a feature of hypertrophy in all-mammalian species and is a prognostic indicator for clinical severity of disease. So far, numerous pathophysiological stimuli have been identified that can induce cardiac hypertrophy, for example mechanical stress, G-protein coupled receptor (GPCR) agonists (including endothelin-1, human urotensin Ⅱ, and angiotensin-Ⅱ), cytokines, and growth factors. Many intracellular signalling pathways have also been implicated; including the mitogen-activated protein kinases (MAPKs), protein
kinase C (PKC), phosphatidyl inositol 3 kinase (PI3 K) -Akt, Janus kinase - Signal Transducers and Activators of Transcription (JAK-STAT), interleukin 6 -interleukin 6 receptor - glycoprotein 130 (IL6-IL6R-gpl30). Recently, calcineurin has attracted great attention as a mediator of Ca2+ -induced cardiac hypertrophy. Over expression of constitutively active mutants of calcineurin and of its downstream transcription factor, nuclear factor of activated T-cells (NFAT3) induced marked cardiac hypertrophy in transgenic mice. The calcineurin inhibitors cyclosporin A and FK506 suppressed phenylephrine- and angiotensin II -induced cardiomyocyte hypertrophy in vitro. All these proved that calcineurin signalling pathway is important for cardiac hypertrophy and heart failure.Our previous study used a tissue bath method to investigate the role of G-protein coupled receptor (GPCR) agonists, including endothelin - 1 (ET-1), angiotensin - II (Ang-II), and human urotensin - II (hUII), on calcineurin activity in human heart. Results showed that all these agonists can significantly increased calcineurin activity. This raised a question, "what's the mechanism by which calcineurin activity was increased?"Aim: The purpose of this study was to investigate the mechanism by which GPCR agonists increase calcineurin activity. Before study we made three working hypothesises that might explain increased calcineurin activity following agonist stimulation. First one: GPCR agonists increase calcineurin activity by increase its protein expression; Second one: after activated by GPCR agonists, PKC phosphorylate some proteins, which also were substrates of calcienurin, increase the calcineurin-mediate free phosphates formation. Thereby increase "calcineurin activity"; the last one: after stimulated by GPCR agonists, calcineurin can be limited proteolysed into constitutively active form, and no need Ca2+/calmodulin for its activity. Calpain is a strong candidate of the enzymes responsible for the post-translational modification of calcineurin.Methods and Results: We examined in the study the possible mechanism by
which GPCR agonists stimulate calcineurin activity in human heart.Patient Population: Tissue from left and right ventricles was obtained from terminal heart failure patients (n=12) undergoing heart transplantation. They were diagnosed with ischaemic heart disease (IHD) (n=5), idiopathic dilated cardiomyopathy (IDC) (n=3), familial dilated cardiomyopathy (n=l), single ventricle with Damus connection (n=l), aortic valve disease (AVD) (n=l), and Becker's syndrome (n=l). All patients had left ventricular dysfunction and elevated left ventricular end diastolic pressure. In some patients, the increased LV pressure was transmitted to the right side of the heart (mean right ventricular systolic pressure 49.5±3.5mmHg), and all patients had right ventricular dysfunction as determined by echocardiogram.The donor hearts that served as the "controls" (n=5) were obtained from subjects who had died from non-cardiac disease related causes, for example victims of vehicle accidents. Their clinical data were unclear.Methods: Several molecular biological technics, such as Western blot, immunohistochemistry, cell culture, zymography, and BioMol calcineurin activity assay, et al were employed in the study.1. Western Blot: In order to know whether calcineurin activity was infected by its protein express, and whether protein expression was related to its distribution, state of heart function, aetiology, and agonists stimulation, we using Western blot method compared calcineurin protein expression between left and right ventricle, failing right ventricle and "donor" right ventricle, right ventricle before and after agonists stimulation in Tissue bath experiment, right ventricle of low and high basal calcineurin activity determined in Tissue bath exprement.2. Immunohistochemistry: Calcineurin is widely distributed in various mammalian tissues. Its concentration in brain is 10-20 times greater than in other tissues and constitutes about 1% of the total protein concentration. It has been learned more and more about the distribution of calcineurin in nerves system, such as 50-70% of calcineurin is bound to membranous or cytoskeletal elements, almost exclusively neuronal distribution of calcineurin in the brain of
different species, CnAa is located in the nuclei while CnAfi is located in the cytoplasm, et al. Compared to the neuronal system, very little is known about the distribution of calcineurin in heart. Heart contains a heterogeneous population of cell types, including cardiomyocytes, fibroblasts, smooth muscle cells, epicardial mesothelial cells, endocardial and vascular endothelial cells, and inflammatory cells. In which cell type does calcineurin expressed? We'll using immunohistochemistry technic to investigate about these.3. Calcineurin activity assay: By calcineurin activity assay to explore the contribution of PKC and calpain to calcineurin activation. Different isoforms of recombinant PKC, calcineurin, and purified calpain were used in this study. To specify PKC and calpain action, we use okadaic acid (OA) to inhibit other phosphatases, such as PP1 and PP2A. Calpain inhibitor leupeptin was used to prove calpain function. In addition, we also investigated the calcium dependence of calpain activation.4. Zymography: Zymography was performed to see the calpain activity in human heart.5. Cell Culture: Cardiac fibroblasts were grown from abdominal aortic artery. Stimulated by ET-1 and hUII respectively in different time. Observe the changes of calcineurin activity and protein fragments.Results:1. Calcineurin activity was independent of protein expression. And protein expression does not influenced by aetiology, ventricle location, and short time agonist stimulation.2. The current study showed that calcineurin was expressed in cardiac myocytes and fibroblasts, a finding consistent with the reported role of calcineurin in myocardial hypertrophy and fibrosis. Staining was also detected in epicardial mesothelial cells, although the role of calcineurin at the surface of the heart is not known. No staining was found in vascular endothelial or smooth muscle cells.3. Different isoforms of PKC have different effect on calcineurin activity. PKCe
really can increase calcineurin activity by increase calcineurin substrates. While in samples that were pre-incubated with PKCaPy, a non-significant increase trend for basal (no PKC) calcineurin-dependent free phosphate formation was observed.4. Calpain expressed in human ventricle.5. Both PKC and calcineurin were substrate of calpain. Requirement of calpain I and calpain II for Ca2+ was different, the truncation products of calcineurin were not same for calpain I and calpain II. An apparent molecular mass of 45 KDa was generated in the calpain I treated sample, whereas smaller cleavage fragments were detected using calpain II. After proteolysis, calcineurin becomes constitutively active form, which no need Ca2+/calmodulin for activation.6. The ability of GPCR agonists to stimulate calpain-dependent activation of calcineurin was investigated. However, protein concentration was too low to detect calcineurin bands.Results show that: 1. calcineurin expression was independent of calcineurin activity; 2. PKCs really increase "calcineurin activity" by increase calcineurin substrates; 3. Both calcineurin and PKC are substrates of calpain. After limited proteolysis, calcineurin activity can be increased significantly, which no need Ca2+/calmodulin for its activation.Conclusion: The mechanism of GPCR agonists increase calcineurin activity was related to PKC and calpain, and was independent of calcineurin expression. After stimulation by GPCR agonists, PKC increase calcineurin activity by increase calcineurin substrates; while calpain by limited proteolysis of calcineurin. After proteolysis, calcineurin was no need Ca2+/calmodulin for its activation.New points of this study: Recent years, the knowledge about Ca2+_ calcineurin _ NFAT signalling pathway in cardiac hypertrophy and heart failure has been learned more and more. However, about the mechanism by which calcineurin
was activated was still unknown. This study is the first attempt to explain it. These hypothesises were made before investigation. Two of them were proved by this study, and one got negative result. Anyway, together all the results, it will be a good contribution to complete the mechanism of hypertrophy and heart failure. We may provide theory basis for prevent cardiac hypertrophy.
心力衰竭是不同病因所致的心脏病发展的最终结局。目前对心力衰竭的防治虽取得了不少进展,但其患病率和死亡率仍居高不下,因而进一步加强心力衰竭的防治研究有着重大的意义。心肌肥厚是临床上发生心力衰竭的前期表现,是心肌为了满足不断增加的心脏做功需要而发生的代偿性变化,这种变化在短时间内可维持或增加心输出量。但心肌肥厚也会增加心肌耗氧量,降低冠状动脉血流储备,长期的供需失衡将会使“代偿性”肥厚逐渐发展为“失代偿性”肥厚,如果再同时合并心肌纤维化和细胞凋亡,最终将导致心功能下降而出现心衰的临床表现。因此,探讨心肌肥厚发生机制以及如何进展为心力衰竭非常重要,可能由此而发现新的心力衰竭防治措施。
心肌肥厚的病理变化包括基因转录和蛋白合成增加,以及肌原纤维重新组装,多数合并胚胎基因表达增加,包括利钠肽和胎儿收缩蛋白基因。利钠肽基因的出现是所有哺乳动物心肌肥厚的特征,也是临床上判断疾病严重程度的预测指标。迄今为止,已发现了许多可引起心肌肥厚的病理生理刺激因子,如机械应力、G-蛋白偶联受体(GPCR)激动剂(包括内皮素-1、人尿压素Ⅱ、血管紧张素-Ⅱ)、细胞因子和生长因子。这些刺激因子涉及到许多细胞内信号传导通路,包括丝裂原活化蛋白激酶(MAPK)、蛋白激酶C(PKC)、磷脂酰肌醇3-激酶(PI3-K)-Akt(又称蛋白激酶B)、Janus激酶-信号传导与转录活化因子(JAK-STAT)和白介素6-白介素6受体-糖蛋白130(IL6-IL6R-gp130)。近年来,钙调神经磷酸酶(Calcineurin)作为Ca~(2+)-介导造成心肌肥厚的重要调
Background: Heart failure is an important and growing public health problem and the cause of substantial morbidity and mortality. Hypertrophy is an early event in the clinical course of heart failure. In response to increased cardiac work demand, the heart increases muscle mass thereby providing temporary maintenance of cardiac output. In short term hypertrophy maintains or increases cardiac output. So it can be viewed as a "beneficial" compensatory response. However, hypertrophy also increases oxygen consumption and reduces coronary blood-flow reserve. This supply-demand mismatch may lead the patient to angina pectoris, MI, arrhythmia or sudden death. In addition, during the process of hypertrophy, cardiac fibrosis and apoptosis may occur simultaneously. All these co-existing pathologies mediate the eventual decline in myocardial function and lead to congestive heart failure. So, the investigation of mechanisms for cardiac hypertrophy and its progression to heart failure is very important, as this may lead to the development of new therapeutic modalities and better guidelines for the prevention of cardiac disease.Pathological changes resulting in cardiac hypertrophy include the increase of gene transcription, protein synthesis, and myofibril assembly. In most forms of cardiac hypertrophy, there is an increase in the expression of embryonic genes, including the genes of natriuretic peptides and fetal contractile proteins. The induction of the natriuretic peptide genes is a feature of hypertrophy in all-mammalian species and is a prognostic indicator for clinical severity of disease. So far, numerous pathophysiological stimuli have been identified that can induce cardiac hypertrophy, for example mechanical stress, G-protein coupled receptor (GPCR) agonists (including endothelin-1, human urotensin Ⅱ, and angiotensin-Ⅱ), cytokines, and growth factors. Many intracellular signalling pathways have also been implicated; including the mitogen-activated protein kinases (MAPKs), protein
kinase C (PKC), phosphatidyl inositol 3 kinase (PI3 K) -Akt, Janus kinase - Signal Transducers and Activators of Transcription (JAK-STAT), interleukin 6 -interleukin 6 receptor - glycoprotein 130 (IL6-IL6R-gpl30). Recently, calcineurin has attracted great attention as a mediator of Ca2+ -induced cardiac hypertrophy. Over expression of constitutively active mutants of calcineurin and of its downstream transcription factor, nuclear factor of activated T-cells (NFAT3) induced marked cardiac hypertrophy in transgenic mice. The calcineurin inhibitors cyclosporin A and FK506 suppressed phenylephrine- and angiotensin II -induced cardiomyocyte hypertrophy in vitro. All these proved that calcineurin signalling pathway is important for cardiac hypertrophy and heart failure.Our previous study used a tissue bath method to investigate the role of G-protein coupled receptor (GPCR) agonists, including endothelin - 1 (ET-1), angiotensin - II (Ang-II), and human urotensin - II (hUII), on calcineurin activity in human heart. Results showed that all these agonists can significantly increased calcineurin activity. This raised a question, "what's the mechanism by which calcineurin activity was increased?"Aim: The purpose of this study was to investigate the mechanism by which GPCR agonists increase calcineurin activity. Before study we made three working hypothesises that might explain increased calcineurin activity following agonist stimulation. First one: GPCR agonists increase calcineurin activity by increase its protein expression; Second one: after activated by GPCR agonists, PKC phosphorylate some proteins, which also were substrates of calcienurin, increase the calcineurin-mediate free phosphates formation. Thereby increase "calcineurin activity"; the last one: after stimulated by GPCR agonists, calcineurin can be limited proteolysed into constitutively active form, and no need Ca2+/calmodulin for its activity. Calpain is a strong candidate of the enzymes responsible for the post-translational modification of calcineurin.Methods and Results: We examined in the study the possible mechanism by
which GPCR agonists stimulate calcineurin activity in human heart.Patient Population: Tissue from left and right ventricles was obtained from terminal heart failure patients (n=12) undergoing heart transplantation. They were diagnosed with ischaemic heart disease (IHD) (n=5), idiopathic dilated cardiomyopathy (IDC) (n=3), familial dilated cardiomyopathy (n=l), single ventricle with Damus connection (n=l), aortic valve disease (AVD) (n=l), and Becker's syndrome (n=l). All patients had left ventricular dysfunction and elevated left ventricular end diastolic pressure. In some patients, the increased LV pressure was transmitted to the right side of the heart (mean right ventricular systolic pressure 49.5±3.5mmHg), and all patients had right ventricular dysfunction as determined by echocardiogram.The donor hearts that served as the "controls" (n=5) were obtained from subjects who had died from non-cardiac disease related causes, for example victims of vehicle accidents. Their clinical data were unclear.Methods: Several molecular biological technics, such as Western blot, immunohistochemistry, cell culture, zymography, and BioMol calcineurin activity assay, et al were employed in the study.1. Western Blot: In order to know whether calcineurin activity was infected by its protein express, and whether protein expression was related to its distribution, state of heart function, aetiology, and agonists stimulation, we using Western blot method compared calcineurin protein expression between left and right ventricle, failing right ventricle and "donor" right ventricle, right ventricle before and after agonists stimulation in Tissue bath experiment, right ventricle of low and high basal calcineurin activity determined in Tissue bath exprement.2. Immunohistochemistry: Calcineurin is widely distributed in various mammalian tissues. Its concentration in brain is 10-20 times greater than in other tissues and constitutes about 1% of the total protein concentration. It has been learned more and more about the distribution of calcineurin in nerves system, such as 50-70% of calcineurin is bound to membranous or cytoskeletal elements, almost exclusively neuronal distribution of calcineurin in the brain of
different species, CnAa is located in the nuclei while CnAfi is located in the cytoplasm, et al. Compared to the neuronal system, very little is known about the distribution of calcineurin in heart. Heart contains a heterogeneous population of cell types, including cardiomyocytes, fibroblasts, smooth muscle cells, epicardial mesothelial cells, endocardial and vascular endothelial cells, and inflammatory cells. In which cell type does calcineurin expressed? We'll using immunohistochemistry technic to investigate about these.3. Calcineurin activity assay: By calcineurin activity assay to explore the contribution of PKC and calpain to calcineurin activation. Different isoforms of recombinant PKC, calcineurin, and purified calpain were used in this study. To specify PKC and calpain action, we use okadaic acid (OA) to inhibit other phosphatases, such as PP1 and PP2A. Calpain inhibitor leupeptin was used to prove calpain function. In addition, we also investigated the calcium dependence of calpain activation.4. Zymography: Zymography was performed to see the calpain activity in human heart.5. Cell Culture: Cardiac fibroblasts were grown from abdominal aortic artery. Stimulated by ET-1 and hUII respectively in different time. Observe the changes of calcineurin activity and protein fragments.Results:1. Calcineurin activity was independent of protein expression. And protein expression does not influenced by aetiology, ventricle location, and short time agonist stimulation.2. The current study showed that calcineurin was expressed in cardiac myocytes and fibroblasts, a finding consistent with the reported role of calcineurin in myocardial hypertrophy and fibrosis. Staining was also detected in epicardial mesothelial cells, although the role of calcineurin at the surface of the heart is not known. No staining was found in vascular endothelial or smooth muscle cells.3. Different isoforms of PKC have different effect on calcineurin activity. PKCe
really can increase calcineurin activity by increase calcineurin substrates. While in samples that were pre-incubated with PKCaPy, a non-significant increase trend for basal (no PKC) calcineurin-dependent free phosphate formation was observed.4. Calpain expressed in human ventricle.5. Both PKC and calcineurin were substrate of calpain. Requirement of calpain I and calpain II for Ca2+ was different, the truncation products of calcineurin were not same for calpain I and calpain II. An apparent molecular mass of 45 KDa was generated in the calpain I treated sample, whereas smaller cleavage fragments were detected using calpain II. After proteolysis, calcineurin becomes constitutively active form, which no need Ca2+/calmodulin for activation.6. The ability of GPCR agonists to stimulate calpain-dependent activation of calcineurin was investigated. However, protein concentration was too low to detect calcineurin bands.Results show that: 1. calcineurin expression was independent of calcineurin activity; 2. PKCs really increase "calcineurin activity" by increase calcineurin substrates; 3. Both calcineurin and PKC are substrates of calpain. After limited proteolysis, calcineurin activity can be increased significantly, which no need Ca2+/calmodulin for its activation.Conclusion: The mechanism of GPCR agonists increase calcineurin activity was related to PKC and calpain, and was independent of calcineurin expression. After stimulation by GPCR agonists, PKC increase calcineurin activity by increase calcineurin substrates; while calpain by limited proteolysis of calcineurin. After proteolysis, calcineurin was no need Ca2+/calmodulin for its activation.New points of this study: Recent years, the knowledge about Ca2+_ calcineurin _ NFAT signalling pathway in cardiac hypertrophy and heart failure has been learned more and more. However, about the mechanism by which calcineurin
was activated was still unknown. This study is the first attempt to explain it. These hypothesises were made before investigation. Two of them were proved by this study, and one got negative result. Anyway, together all the results, it will be a good contribution to complete the mechanism of hypertrophy and heart failure. We may provide theory basis for prevent cardiac hypertrophy.
引文
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