人SIRT1H363Y心脏特异转基因小鼠的建立及其导致扩张型心肌病和心力衰竭的机制研究
摘要
随着社会老龄人口逐渐增加,心力衰竭已经成为最为重要的心血管问题,也成为人们最为关心的健康问题之一。研究表明在扩张型心肌病中心肌细胞凋亡大量增加,导致心脏逐渐发展成为心力衰竭:心肌细胞凋亡也是发生扩张型心肌病和心力衰竭一个主要事件和中心机制。去乙酰化酶Sir2α(the murine ortholog of silent informationregulator 2)敲除的小鼠发生心脏发育缺陷,只有很少一部分敲除鼠可以存活下来;Sir2α对于氧化应激导致的心肌细胞凋亡具有保护作用。更重要的是:体外研究表明位点突变型的Sir2α(SIR2H355A)可以增加基础水平和过氧化氢诱导的心肌细胞凋亡,但是在心脏中SIRT1去乙酰化酶的作用还仍然不清楚。
我们猜测:抑制心肌细胞中SIRT1的去乙酰化酶活性可以增加心肌细胞凋亡,导致心脏的功能失常。为了验证这个假说,我们进行了如下的研究:
首先,在压力负荷导致大鼠心肌肥厚和心力衰竭模型心脏中检测SIRT1的表达,发现其表达相对于对照组表达显著增加。为了研究SIRT1的去乙酰化酶活性在体内的功能,将位点突变型的SIRT1(SIRT1H363Y)cDNA与α-MHC启动子连接,通过显微注射受精卵的方法制备了心脏特异性表达SIRT1H363Y的转基因小鼠,经过RT-PCR、Southern Blot、Western blot和免疫组织化学等方法证明SIRT1H3636Y在转基因小鼠心脏组织中特异性高表达。然而出乎意料的是:转基因小鼠心房和心室扩张,并且绝大部分在一周到一个月内死亡;幸运地,我们得到三株转基因小鼠能够产生后代,但是这些后代大部分在8到12天内死亡。转基因小鼠心脏重量和体重的比例显著高于阴性同窝小鼠。分别用病理、超声心动图和分子检测诊断表明转基因小鼠发生扩张型心肌病;电子显微镜显示线粒体结构明显破坏和肌小节变性与降解;用TUNNEL方法进行凋亡分析发现转基因小鼠的心肌细胞发生凋亡的细胞数目显著多于阴性同窝小鼠。对于心肌细胞凋亡机制的研究发现转基因小鼠心脏中Bax的表达显著高于阴性同窝小鼠,同时Caspase-9发生显著剪切和Apaf-1的表达显著增高;而c-FLIP和Caspase-8并没有明显的改变。因此,Bax介导的线粒体途径的凋亡通路在转基因小鼠心肌细胞凋亡中起到主要作用。进一步研究SIRT1H363Y和Bax介导的细胞凋亡之间的内在关系,我们发现p53的乙酰化水平显著增加:在细胞水平,通过腺病毒过表达突变型的SIRT1(ad-SIRT1H363Y)同样可以导致原代培养心肌细胞中p53的乙酰化水平和Bax的表达显著增加。
综合上述结果可以得出结论:利用α-MHC启动子可以使SIRT1H363Y在心肌细胞中高表达。心脏组织特异性过表达SIRT1H363Y显著增加了心肌细胞凋亡,导致心脏在早期就发生严重的扩张型心肌病,进而迅速影响心脏功能,最终导致心力衰竭和早期致死。
Heart failure has become the most important cardiovascular health problem worldwide and will probably become a major concern as the aging population grows in size. Cardiomyocyte apoptosis is greatly increased in dilated cardiomyopathy which is characterized by the gradual development of heart failure.Several studies have subsequently suggested that cardiomyocyte apoptosis is a key event and a central mechanism in the development of dilated cardiomyopathy and heart failure.Both the intrinsic(mitochondrial) and the extrinsic(death receptor mediated) pathway have been shown to activate caspase-3.Activation of caspase-3 is followed by cardiomyocyte apoptosis,which is sufficient to induce dilated cardiomyopathy and heart failure.Recently, loss of a basal survival mechanism has been noted to undergo apoptosis in various animal models of heart failure.Chronically elevated but low levels of apoptosis may play a causal role in the pathogenesis of dilated cardiomyopathy and heart failure.
SIRT1,the mammalian ortholog of Sir2,is a NAD-dependent deacetylase belonging to the classⅢhistone deacetylase(HDAC) family and functions in a wide array of cellular processes,including gene silencing,longevity,muscle differentiation,and DNA damage repair.Sir2αoverexpression was shown to inhibit p53 transcriptional activity and p53-dependent apoptosis in response to DNA damage and oxidative stresses.SIRT1 also inhibits apoptosis and promotes DNA repair by deacetylating FOXO transcription factors. However,a point mutation at the highly conserved histidine residue at the core domain (SIRT1-363Y) effectively abolished the deacetylase activity and overexpression of this catalytically inactive Sir2αprotein potentiated these cellular stress responses.Mice deficient in Sir2αexhibit developmental abnormality in the heart and only infrequently survive postnatally.Recent published data indicate that SIRT1 plays an essential role in mediating survival of cardiomyocytes under stress in vitro.Importantly,dominant negative Sir2αwhich express mouse Sir2H355A in neonatal rat ventricular myocytes has been showed to enhance basic cell death as well as slightly potentiating hydrogen peroxide-induced cell death,but in vivo the function of the deacetylase activity of SIRT1 in the heart is still largely unknown.
We develop our hypothesis that cardiac overexpression of dominant Negative SIRT1 in cardiomyocytes can induce cardiac apoptosis and cause cardiac dysfunction.We carried out the following experiments to test the hypothesis.
SIRT1 expression is up-regulated in the failing heart induced by 8 weeks of pressure overload.In an attempt to determine the requirement for the deacetylase activity of SIRT1 in the heart,we generated transgenic(TG) mice with cardiac-specific expression of a dominant negative form of SIRT1(SIRT1H363Y).Reverse transcription polymerase chain reaction(RT-PCR),Western blot and Immunohistochemistry show that SIRT1H363Y was properly expressed in cardiomyocytes.Unexpectedly,these mice exhibiting cardiac specific dominant negative SIRT1 overexpression had dilated atrial and ventricular chambers and lead to premature death and died from one week to four weeks after birth. Fortunately,three lines of TG founder mice survived to generate TG-positive offspring, and their offspring died mainly from postnatal days 8 to 12.The heart weight/body weight ratio of transgenic mice was significantly higher compared with nontransgenic mice. Pathology,echocardiography and molecular phenotype confirmed a dilated cardiomyopathy.Electronic microscopy revealed mitochondrial deterioration in hearts of transgenic mice and myofilaments degeneration in some limited regions of the hearts. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed greater abundance of apoptotic nuclei in TG mice hearts.To further investigate the mechanism of apoptosis in TG mice hearts,we found that the level of Bax protein was significantly increased.The level of Apaf-1 protein and the cleavage of Caspase-9 were significantly increased in transgenic mice hearts,whereas the protein abundance of c-FLIP and Caspase-8 were similar with WT controls.These data suggest that increased apoptosis in TG mice hearts is predominantly due to increased Bax-mediated mitochondria apoptosis pathway rather than FasL/TNF signaling pathway.To further examine potential connections between SIRT1H363Y and Bax-mediated apoptosis,we found that the level of p53 acetylation was upregulated upon dominant negative SIRT1 overexpression. Consistent with results in TG mice,adenoviral expression of SIRT1H363Y significantly upregulated Bax protein in neonatal rat ventricular myocytes,and the level of p53 acetylation was increased upon adenoviral SIRT1H363Y overexpression.
In the present study,we generated TG mice exhibiting cardiac dominant negative SIRT1 overexpression using theα-myosin heavy chain(α-MHC) promoter.Cardiac overexpression of dominant negative SIRT1 is sufficient to cause cardiomyocytes apoptosis and dilated cardiomyopathy leading to a rapid deterioration in cardiac function and death in the early postnatal period.
我们猜测:抑制心肌细胞中SIRT1的去乙酰化酶活性可以增加心肌细胞凋亡,导致心脏的功能失常。为了验证这个假说,我们进行了如下的研究:
首先,在压力负荷导致大鼠心肌肥厚和心力衰竭模型心脏中检测SIRT1的表达,发现其表达相对于对照组表达显著增加。为了研究SIRT1的去乙酰化酶活性在体内的功能,将位点突变型的SIRT1(SIRT1H363Y)cDNA与α-MHC启动子连接,通过显微注射受精卵的方法制备了心脏特异性表达SIRT1H363Y的转基因小鼠,经过RT-PCR、Southern Blot、Western blot和免疫组织化学等方法证明SIRT1H3636Y在转基因小鼠心脏组织中特异性高表达。然而出乎意料的是:转基因小鼠心房和心室扩张,并且绝大部分在一周到一个月内死亡;幸运地,我们得到三株转基因小鼠能够产生后代,但是这些后代大部分在8到12天内死亡。转基因小鼠心脏重量和体重的比例显著高于阴性同窝小鼠。分别用病理、超声心动图和分子检测诊断表明转基因小鼠发生扩张型心肌病;电子显微镜显示线粒体结构明显破坏和肌小节变性与降解;用TUNNEL方法进行凋亡分析发现转基因小鼠的心肌细胞发生凋亡的细胞数目显著多于阴性同窝小鼠。对于心肌细胞凋亡机制的研究发现转基因小鼠心脏中Bax的表达显著高于阴性同窝小鼠,同时Caspase-9发生显著剪切和Apaf-1的表达显著增高;而c-FLIP和Caspase-8并没有明显的改变。因此,Bax介导的线粒体途径的凋亡通路在转基因小鼠心肌细胞凋亡中起到主要作用。进一步研究SIRT1H363Y和Bax介导的细胞凋亡之间的内在关系,我们发现p53的乙酰化水平显著增加:在细胞水平,通过腺病毒过表达突变型的SIRT1(ad-SIRT1H363Y)同样可以导致原代培养心肌细胞中p53的乙酰化水平和Bax的表达显著增加。
综合上述结果可以得出结论:利用α-MHC启动子可以使SIRT1H363Y在心肌细胞中高表达。心脏组织特异性过表达SIRT1H363Y显著增加了心肌细胞凋亡,导致心脏在早期就发生严重的扩张型心肌病,进而迅速影响心脏功能,最终导致心力衰竭和早期致死。
Heart failure has become the most important cardiovascular health problem worldwide and will probably become a major concern as the aging population grows in size. Cardiomyocyte apoptosis is greatly increased in dilated cardiomyopathy which is characterized by the gradual development of heart failure.Several studies have subsequently suggested that cardiomyocyte apoptosis is a key event and a central mechanism in the development of dilated cardiomyopathy and heart failure.Both the intrinsic(mitochondrial) and the extrinsic(death receptor mediated) pathway have been shown to activate caspase-3.Activation of caspase-3 is followed by cardiomyocyte apoptosis,which is sufficient to induce dilated cardiomyopathy and heart failure.Recently, loss of a basal survival mechanism has been noted to undergo apoptosis in various animal models of heart failure.Chronically elevated but low levels of apoptosis may play a causal role in the pathogenesis of dilated cardiomyopathy and heart failure.
SIRT1,the mammalian ortholog of Sir2,is a NAD-dependent deacetylase belonging to the classⅢhistone deacetylase(HDAC) family and functions in a wide array of cellular processes,including gene silencing,longevity,muscle differentiation,and DNA damage repair.Sir2αoverexpression was shown to inhibit p53 transcriptional activity and p53-dependent apoptosis in response to DNA damage and oxidative stresses.SIRT1 also inhibits apoptosis and promotes DNA repair by deacetylating FOXO transcription factors. However,a point mutation at the highly conserved histidine residue at the core domain (SIRT1-363Y) effectively abolished the deacetylase activity and overexpression of this catalytically inactive Sir2αprotein potentiated these cellular stress responses.Mice deficient in Sir2αexhibit developmental abnormality in the heart and only infrequently survive postnatally.Recent published data indicate that SIRT1 plays an essential role in mediating survival of cardiomyocytes under stress in vitro.Importantly,dominant negative Sir2αwhich express mouse Sir2H355A in neonatal rat ventricular myocytes has been showed to enhance basic cell death as well as slightly potentiating hydrogen peroxide-induced cell death,but in vivo the function of the deacetylase activity of SIRT1 in the heart is still largely unknown.
We develop our hypothesis that cardiac overexpression of dominant Negative SIRT1 in cardiomyocytes can induce cardiac apoptosis and cause cardiac dysfunction.We carried out the following experiments to test the hypothesis.
SIRT1 expression is up-regulated in the failing heart induced by 8 weeks of pressure overload.In an attempt to determine the requirement for the deacetylase activity of SIRT1 in the heart,we generated transgenic(TG) mice with cardiac-specific expression of a dominant negative form of SIRT1(SIRT1H363Y).Reverse transcription polymerase chain reaction(RT-PCR),Western blot and Immunohistochemistry show that SIRT1H363Y was properly expressed in cardiomyocytes.Unexpectedly,these mice exhibiting cardiac specific dominant negative SIRT1 overexpression had dilated atrial and ventricular chambers and lead to premature death and died from one week to four weeks after birth. Fortunately,three lines of TG founder mice survived to generate TG-positive offspring, and their offspring died mainly from postnatal days 8 to 12.The heart weight/body weight ratio of transgenic mice was significantly higher compared with nontransgenic mice. Pathology,echocardiography and molecular phenotype confirmed a dilated cardiomyopathy.Electronic microscopy revealed mitochondrial deterioration in hearts of transgenic mice and myofilaments degeneration in some limited regions of the hearts. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed greater abundance of apoptotic nuclei in TG mice hearts.To further investigate the mechanism of apoptosis in TG mice hearts,we found that the level of Bax protein was significantly increased.The level of Apaf-1 protein and the cleavage of Caspase-9 were significantly increased in transgenic mice hearts,whereas the protein abundance of c-FLIP and Caspase-8 were similar with WT controls.These data suggest that increased apoptosis in TG mice hearts is predominantly due to increased Bax-mediated mitochondria apoptosis pathway rather than FasL/TNF signaling pathway.To further examine potential connections between SIRT1H363Y and Bax-mediated apoptosis,we found that the level of p53 acetylation was upregulated upon dominant negative SIRT1 overexpression. Consistent with results in TG mice,adenoviral expression of SIRT1H363Y significantly upregulated Bax protein in neonatal rat ventricular myocytes,and the level of p53 acetylation was increased upon adenoviral SIRT1H363Y overexpression.
In the present study,we generated TG mice exhibiting cardiac dominant negative SIRT1 overexpression using theα-myosin heavy chain(α-MHC) promoter.Cardiac overexpression of dominant negative SIRT1 is sufficient to cause cardiomyocytes apoptosis and dilated cardiomyopathy leading to a rapid deterioration in cardiac function and death in the early postnatal period.
引文
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