慢性心衰急性失代偿的分子机制与治疗的分子基础
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摘要
随慢性心力衰竭（chronic heart failure, CHF）患者数量逐渐增加，慢性心力衰竭急性失代偿（acute decompensated heart failure, ADHF）和急性心力衰竭发作，业已成为心衰患者住院的主因，而且几乎2/3的病例是由于ADHF所致。在我国的调查中显示：导致ADHF最常见的诱因是感染。而老年患者以革兰氏阴性菌感染为主，其细胞壁中的脂多糖（lipopolysaccharide, LPS）起关键作用。故本实验拟用LPS诱导慢性心衰小鼠建立ADHF模型，探讨炎性细胞因子及信号通路分子在ADHF中的相互关系。近来研究证实，促红细胞生成素能通过特定靶向NF- B激活炎症途径降低致病细菌引起全身性感染的能力，对心、脑等脏器有明显的保护作用。本研究拟观察EPO在ADHF阶段是否有保护作用，初步分析其作用的分子基础。
实验分为两步进行，第一步：用阿霉素（doxorubicin, DOX）腹腔注射建立CHF模型，再腹腔注射LPS诱导建立ADHF模型观察全身炎症与信号通路分子变化，将50只雄性C57Bl/6小鼠随机分为Nor组、Dox组、D&L组、Lps组。给予Dox组、D&L组腹腔注射DOX，每次5 mg·kg~(-1)，1周1次，共6w，累积总剂量30 mg·kg~(-1)建立CHF小鼠模型，第7周给予Lps组、D&L组腹腔注射LPS 5mg·kg~(-1)，建立ADHF模型；一周后进行心脏超声检查、ELISA法测定血浆中IL-6含量、免疫组织化学分析心肌组织切片中的p-STAT3、Bcl-2、Bax蛋白表达，并用Image ProPlus 6.0图像分析系统将图片转为定量数据，然后做统计学分析。第二步：用上述方法建立ADHF模型后，再腹腔注射促红细胞生成素（erythropoietin, EPO），观察EPO在ADHF阶段是否有保护作用，初步分析其作用的全身炎症与信号通路分子改变。将50只C57Bl/6小鼠随机分为Nor组、Dox组、D&L组、D&E组和DLE组，每组10只。用上述方式建立ADHF模型，第7周给予D&L组和DLE组注射LPS，同时给予D&E和DLE组腹腔注射单剂EPO 5 000 iu·kg-1。观察1周后，第8周行心脏超声检查、ELISA法测定血浆中白介素-6（IL-6）和脑钠肽（BNP）含量、心重指数、免疫组织化学分析心肌组织切片中的p-STAT3、Bcl-2、Bax蛋白表达，并用Image ProPlus 6.0图像分析系统将图片转为定量数据，然后做统计学分析。
经上述过程得出以下试验结果，第一部分：与Nor组相比较，Dox组小鼠舒张期左室后壁厚度(posterior left ventricular wall, PWTd)、左室收缩末内径(left ventricular end systolic dimension, LVESd)明显升高，左室舒张末内径(left ventricular end diastolic dimension, LVEDd)和短轴缩短率(shortening fraction, FS)明显下降。与Dox组相比较，D&L组LVEDd和LVESd显著升高，而PWTd和FS显著降低，提示心脏体积扩大，心室壁厚度减少，收缩功能受损；而Nor组与Lps组，上述各指标无统计学差异；Dox与Lps组之间血浆IL-6水平无显著差异；Dox、Lps组血浆IL-6水平显著高于Nor组(P＜0.01)；D&L组血浆IL-6水平显著高于Dox组(P<0.01)；与Nor组比较，Lps组Bax、Bcl-2与p-STAT3表达增加(P＜0.05)，Dox组p-STAT3、Bcl-2与Bax表达显著增加(P＜0.05)且Bcl-2表达量较Bax增加明显，D&L组较Dox组，Bax表达显著增加(P＜0.05)，Bcl-2、p-STAT3降低表达减低(P＜0.05)。第二部分：与D&L组相比，DLE组小鼠给予EPO处理后心室壁厚度、FS也明显增高(P<0.01)；DLE组血浆IL-6水平较D&L组无显著变化，DLE组血浆BNP水平较D&L组显著降低(P＜0.05)；DLE组较D&L组Bcl-2和p-STAT3明显增加(P＜0.05)，Bax明显降低(P＜0.05)。
从第一部分实验可见，注射LPS刺激慢性心衰小鼠后，心肌舒张功能和收缩功能减退，成功建立ADHF模型，而ADHF小鼠血浆中IL-6明显增加，Bcl-2所占比例减少，Bax高出Bcl-2两倍，p-STAT3表达减少，心肌细胞由肥厚转向凋亡。由此可见：心肌细胞JAK-STAT信号通路及其细胞因子信号抑制因子平衡被打乱，导致促心肌凋亡基因表达增加，促进心肌细胞凋亡。而第二部分，向CHF小鼠注射EPO后血浆中炎性因子减少、心肌细胞倾向肥大、心收缩和舒张功能得到明显改善；而向ADHF小鼠注射EPO后心室壁厚度增加、FS值升高，BNP下降,Bax蛋白表达减少,Bcl-2蛋白表达增加,STAT3活化水平升高,却对血浆中IL-6蛋白表达改变不明显,由此推测,EPO可能促使p-STAT3显著增加与细胞因子信号抑制因子建立新的平衡,从而抑制心肌细胞凋亡,对ADHF起到良好的保护作用。
As the increasing number of patients with chronic heart failure, attacksof acute decompensated heart failure and acute heart failure have beenbecoming the main cause of hospitalization in patients with heart failure,and almost two thirds of the patients are caused by ADHF. According tosurveys in our country , the infection is the common inducement of ADHF.While the senile patients’infection is mainly caused by G– bacillius, theLPS in their cell walls plays a key role. ADHF model was established byLPS on mice. To explore the pathology mechanisms of inflammatoryfactors and the rate variation of cell signaling pathway on ADHF model.Recent studies have demonstrated that erythropoietin not can reducesystemic infection disease caused by bacteria by NFκB pathway, but alsoplays significantly protective role to heart, brain and so on. This study is toinvestigate whether EPO has the protective effect on ADHF stage, andpreliminarily to analyse the molecular basis of its role.
Therefore, this experiment was arrangaled into two steps. The firststep: The CHF model was established by intraperitoneal injection of thedoxorubicin, then the ADHF model was induced by LPS, in order toobserve the changes of systemic inflammatory and cell signaling pathway.Fifty male C57B1/6 mice were randomly divided into four groups asfollows: normol (Nor) group, Dox group, D&L group and LPS group. InDox group and D&L group: Each mice was injected intraperitoneally withDOX at a dose of 5 mg·kg-1 body weight once a week. When thecumulative total dose of DOX reached to 30 mg·kg-1, all CHF mice modelswere established. From the seventh week, the mice of LPS group and D&L group were injected intraperitoneally with LPS at a dose of 5 mg·kg~(-1) bodyweight to make ADHF model. After one week, the mice were examined byechocardiogram; the concentration of IL-6 in mice plasma were measuredby ELISA. The protein expressions of p-STAT3, Bcl-2, Bax in themyocardial biopsy were detected by soft ware immunohistochemicalanalysis, and we converted this image to quantitative data by imageProPlus 6.0 , and then did statistical analysis. The second step：ADHFmodel was established as described above, and then we injected EPO toinvestigate whether EPO had a protective effect on ADHF stage, andpreliminarily analysed the molecular basis of its role. Fifty male C57B1/6mice were randomly divided into four group as follows: normol (Nor)group(n=10); Dox group(n=10); D&L group(n=10); D&E group(n=10);ADHF model were builted. On the seventh week , the mice of D&L andDLE were injected with LPS, and the mice of D&E group and DLE groupwere injected with a single dose of EPO at a dose of 5000 iu·kg~(-1).Observed one week, from eighth week on, the mice were examined byechocardiogram; the concentration of IL-6 and brain natriuretic peptidewere determined in plasma. Heart weight index was measured. the proteinexpressions of p-STAT3、Bcl-2、Bax in the myocardial biopsy weredetected by immunohistochemical analysis，and we converted this image toquantitative data by soft ware image ProPlus 6.0 , and then finishedstatistical analysis.
The following conclusin are obtained from the above processes.Thefirst step:compared to Nor group, the PWTd and LVESd in DOX groupmice were obviously higher, while LVEDd and FS was significantly lowerthan that. Compared with DOX group, the LVEDd and LVESd contents inD&L group were largely increased. However the PWTD and FS content inD&L group were decreased significantly. These data suggested mouse’sheart chamber was expanded, ventricular wall was thinner, the systolicfunction was damaged, while the mentioned Nor group and LPS group haven’t statistical significance. There isn’t statistical significance in thelevel of IL-6 of plasma in Dox group and LPS group , however it wassignificantly higher than that of Nor group(P<0.01); The levels of IL-6 ofplasma in D&L group were significantly higher than these of Dox group.Compared with Nor group, the expression of Bax, Bcl-2 and p-stat3 wereincreased, and those of Dox group were significantly increased(P<0.05),and positive rate of Bcl-2 were more significant than Bax; The expressionof Bax in D&L group were more significant than these in Doxgroup(P<0.05), while the expression of Bcl-2 and p-stat3 weredecreased(P<0.05). The results of the second step: Compared to D&Lgroup, the depth of ventricular wall were thinner, and the result of FS weresignificantly increased(P<0.05). There was no difference in statistics levelof IL-6 in plasma between DLE group and D&L group, but the plasmalevel of BNP in DLE group were significantly less than that in D&Lgroup(P<0.05); The expression of Bcl-2 and p-stat3 in DLE group wereobviously increased (P<0.05), while the expression of Bax weresignificantly decreased(P<0.05).
The conclusin can be shown from the first part of the experiment:myocardial systolic and diastolic function of LV in mice with chronic heartfailure after injection of LPS are decreased, suggesting that the model ofADHF mice was established successfully. The level of IL-6 weresignificantly increased in plasma of ADHF mice. The levels of Bcl-2,p-STAT3 decrease and the expression level of Bax was twice more thanthat of Bcl-2 . Cardiomyocyte was induced from hypertrophy to apoptosis.Consequently, the balance between mice myocardium cells JAK-STATsignaling pathway and suppressor of cytokine signaling was disordered asheart failure by LPS, which accelerates the expression of proapoptotict andcontributing to myocardial cells’apoptosis. The conclusin of the secondpart suggested, The plasma levels of inflammatory cytokines were inhibitedafter the mice were injected with EPO, and myocardial cells tend to hypertrophy, cardiac systolic and diastolic function were significantlyimproved. ADHF mice ventricular wall thickness is increased, and theexpression levels of FS was significantly increased .There is no differencein statistics levels of IL-6 in plasma. The expression levels of Bcl-2 andp-stat3 were significantly increased, while the expression levels of Baxwere significantly decreased. Inferring, EPO significantly increases theexpression levels of p-STAT3 and establishes a new balance withsuppressor of cytokine signaling, so inhibits the cardiomyocyte apoptosisand has a good protective effect on ADHF.
实验分为两步进行，第一步：用阿霉素（doxorubicin, DOX）腹腔注射建立CHF模型，再腹腔注射LPS诱导建立ADHF模型观察全身炎症与信号通路分子变化，将50只雄性C57Bl/6小鼠随机分为Nor组、Dox组、D&L组、Lps组。给予Dox组、D&L组腹腔注射DOX，每次5 mg·kg~(-1)，1周1次，共6w，累积总剂量30 mg·kg~(-1)建立CHF小鼠模型，第7周给予Lps组、D&L组腹腔注射LPS 5mg·kg~(-1)，建立ADHF模型；一周后进行心脏超声检查、ELISA法测定血浆中IL-6含量、免疫组织化学分析心肌组织切片中的p-STAT3、Bcl-2、Bax蛋白表达，并用Image ProPlus 6.0图像分析系统将图片转为定量数据，然后做统计学分析。第二步：用上述方法建立ADHF模型后，再腹腔注射促红细胞生成素（erythropoietin, EPO），观察EPO在ADHF阶段是否有保护作用，初步分析其作用的全身炎症与信号通路分子改变。将50只C57Bl/6小鼠随机分为Nor组、Dox组、D&L组、D&E组和DLE组，每组10只。用上述方式建立ADHF模型，第7周给予D&L组和DLE组注射LPS，同时给予D&E和DLE组腹腔注射单剂EPO 5 000 iu·kg-1。观察1周后，第8周行心脏超声检查、ELISA法测定血浆中白介素-6（IL-6）和脑钠肽（BNP）含量、心重指数、免疫组织化学分析心肌组织切片中的p-STAT3、Bcl-2、Bax蛋白表达，并用Image ProPlus 6.0图像分析系统将图片转为定量数据，然后做统计学分析。
经上述过程得出以下试验结果，第一部分：与Nor组相比较，Dox组小鼠舒张期左室后壁厚度(posterior left ventricular wall, PWTd)、左室收缩末内径(left ventricular end systolic dimension, LVESd)明显升高，左室舒张末内径(left ventricular end diastolic dimension, LVEDd)和短轴缩短率(shortening fraction, FS)明显下降。与Dox组相比较，D&L组LVEDd和LVESd显著升高，而PWTd和FS显著降低，提示心脏体积扩大，心室壁厚度减少，收缩功能受损；而Nor组与Lps组，上述各指标无统计学差异；Dox与Lps组之间血浆IL-6水平无显著差异；Dox、Lps组血浆IL-6水平显著高于Nor组(P＜0.01)；D&L组血浆IL-6水平显著高于Dox组(P<0.01)；与Nor组比较，Lps组Bax、Bcl-2与p-STAT3表达增加(P＜0.05)，Dox组p-STAT3、Bcl-2与Bax表达显著增加(P＜0.05)且Bcl-2表达量较Bax增加明显，D&L组较Dox组，Bax表达显著增加(P＜0.05)，Bcl-2、p-STAT3降低表达减低(P＜0.05)。第二部分：与D&L组相比，DLE组小鼠给予EPO处理后心室壁厚度、FS也明显增高(P<0.01)；DLE组血浆IL-6水平较D&L组无显著变化，DLE组血浆BNP水平较D&L组显著降低(P＜0.05)；DLE组较D&L组Bcl-2和p-STAT3明显增加(P＜0.05)，Bax明显降低(P＜0.05)。
从第一部分实验可见，注射LPS刺激慢性心衰小鼠后，心肌舒张功能和收缩功能减退，成功建立ADHF模型，而ADHF小鼠血浆中IL-6明显增加，Bcl-2所占比例减少，Bax高出Bcl-2两倍，p-STAT3表达减少，心肌细胞由肥厚转向凋亡。由此可见：心肌细胞JAK-STAT信号通路及其细胞因子信号抑制因子平衡被打乱，导致促心肌凋亡基因表达增加，促进心肌细胞凋亡。而第二部分，向CHF小鼠注射EPO后血浆中炎性因子减少、心肌细胞倾向肥大、心收缩和舒张功能得到明显改善；而向ADHF小鼠注射EPO后心室壁厚度增加、FS值升高，BNP下降,Bax蛋白表达减少,Bcl-2蛋白表达增加,STAT3活化水平升高,却对血浆中IL-6蛋白表达改变不明显,由此推测,EPO可能促使p-STAT3显著增加与细胞因子信号抑制因子建立新的平衡,从而抑制心肌细胞凋亡,对ADHF起到良好的保护作用。
As the increasing number of patients with chronic heart failure, attacksof acute decompensated heart failure and acute heart failure have beenbecoming the main cause of hospitalization in patients with heart failure,and almost two thirds of the patients are caused by ADHF. According tosurveys in our country , the infection is the common inducement of ADHF.While the senile patients’infection is mainly caused by G– bacillius, theLPS in their cell walls plays a key role. ADHF model was established byLPS on mice. To explore the pathology mechanisms of inflammatoryfactors and the rate variation of cell signaling pathway on ADHF model.Recent studies have demonstrated that erythropoietin not can reducesystemic infection disease caused by bacteria by NFκB pathway, but alsoplays significantly protective role to heart, brain and so on. This study is toinvestigate whether EPO has the protective effect on ADHF stage, andpreliminarily to analyse the molecular basis of its role.
Therefore, this experiment was arrangaled into two steps. The firststep: The CHF model was established by intraperitoneal injection of thedoxorubicin, then the ADHF model was induced by LPS, in order toobserve the changes of systemic inflammatory and cell signaling pathway.Fifty male C57B1/6 mice were randomly divided into four groups asfollows: normol (Nor) group, Dox group, D&L group and LPS group. InDox group and D&L group: Each mice was injected intraperitoneally withDOX at a dose of 5 mg·kg-1 body weight once a week. When thecumulative total dose of DOX reached to 30 mg·kg-1, all CHF mice modelswere established. From the seventh week, the mice of LPS group and D&L group were injected intraperitoneally with LPS at a dose of 5 mg·kg~(-1) bodyweight to make ADHF model. After one week, the mice were examined byechocardiogram; the concentration of IL-6 in mice plasma were measuredby ELISA. The protein expressions of p-STAT3, Bcl-2, Bax in themyocardial biopsy were detected by soft ware immunohistochemicalanalysis, and we converted this image to quantitative data by imageProPlus 6.0 , and then did statistical analysis. The second step：ADHFmodel was established as described above, and then we injected EPO toinvestigate whether EPO had a protective effect on ADHF stage, andpreliminarily analysed the molecular basis of its role. Fifty male C57B1/6mice were randomly divided into four group as follows: normol (Nor)group(n=10); Dox group(n=10); D&L group(n=10); D&E group(n=10);ADHF model were builted. On the seventh week , the mice of D&L andDLE were injected with LPS, and the mice of D&E group and DLE groupwere injected with a single dose of EPO at a dose of 5000 iu·kg~(-1).Observed one week, from eighth week on, the mice were examined byechocardiogram; the concentration of IL-6 and brain natriuretic peptidewere determined in plasma. Heart weight index was measured. the proteinexpressions of p-STAT3、Bcl-2、Bax in the myocardial biopsy weredetected by immunohistochemical analysis，and we converted this image toquantitative data by soft ware image ProPlus 6.0 , and then finishedstatistical analysis.
The following conclusin are obtained from the above processes.Thefirst step:compared to Nor group, the PWTd and LVESd in DOX groupmice were obviously higher, while LVEDd and FS was significantly lowerthan that. Compared with DOX group, the LVEDd and LVESd contents inD&L group were largely increased. However the PWTD and FS content inD&L group were decreased significantly. These data suggested mouse’sheart chamber was expanded, ventricular wall was thinner, the systolicfunction was damaged, while the mentioned Nor group and LPS group haven’t statistical significance. There isn’t statistical significance in thelevel of IL-6 of plasma in Dox group and LPS group , however it wassignificantly higher than that of Nor group(P<0.01); The levels of IL-6 ofplasma in D&L group were significantly higher than these of Dox group.Compared with Nor group, the expression of Bax, Bcl-2 and p-stat3 wereincreased, and those of Dox group were significantly increased(P<0.05),and positive rate of Bcl-2 were more significant than Bax; The expressionof Bax in D&L group were more significant than these in Doxgroup(P<0.05), while the expression of Bcl-2 and p-stat3 weredecreased(P<0.05). The results of the second step: Compared to D&Lgroup, the depth of ventricular wall were thinner, and the result of FS weresignificantly increased(P<0.05). There was no difference in statistics levelof IL-6 in plasma between DLE group and D&L group, but the plasmalevel of BNP in DLE group were significantly less than that in D&Lgroup(P<0.05); The expression of Bcl-2 and p-stat3 in DLE group wereobviously increased (P<0.05), while the expression of Bax weresignificantly decreased(P<0.05).
The conclusin can be shown from the first part of the experiment:myocardial systolic and diastolic function of LV in mice with chronic heartfailure after injection of LPS are decreased, suggesting that the model ofADHF mice was established successfully. The level of IL-6 weresignificantly increased in plasma of ADHF mice. The levels of Bcl-2,p-STAT3 decrease and the expression level of Bax was twice more thanthat of Bcl-2 . Cardiomyocyte was induced from hypertrophy to apoptosis.Consequently, the balance between mice myocardium cells JAK-STATsignaling pathway and suppressor of cytokine signaling was disordered asheart failure by LPS, which accelerates the expression of proapoptotict andcontributing to myocardial cells’apoptosis. The conclusin of the secondpart suggested, The plasma levels of inflammatory cytokines were inhibitedafter the mice were injected with EPO, and myocardial cells tend to hypertrophy, cardiac systolic and diastolic function were significantlyimproved. ADHF mice ventricular wall thickness is increased, and theexpression levels of FS was significantly increased .There is no differencein statistics levels of IL-6 in plasma. The expression levels of Bcl-2 andp-stat3 were significantly increased, while the expression levels of Baxwere significantly decreased. Inferring, EPO significantly increases theexpression levels of p-STAT3 and establishes a new balance withsuppressor of cytokine signaling, so inhibits the cardiomyocyte apoptosisand has a good protective effect on ADHF.
引文
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20.李相良,张灵,张慕淳,等.利用siRNA技术沉默膀胱肿瘤STAT3基因及促进凋亡的机制探讨[J].中国老年学杂志, 2008, 28 (2):131-133。
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22. Morales JK, Falanga YT, Depcrynski A, et al. Mast cell homeostasisand the JAK-STAT pathway [J] . Genes Immun, 2010, 11(8): 599-608.
23. Imada K, Leonard WJ.The Jak-STAT pathway [J] . Mol Immunol,2000, 37(1-2): 1-11.
24. Ihle JN.The STAT family in cytokine signaling [J] . Curr Opin CellBiol, 2001, 13(2): 211-217.
25. Jacoby JJ, Kalinowski A, Liu MG, et al.Cardiomyocyte-restrictedknockout of STAT3 results in higher sensitivity to inflammation,cardiac fibrosis, and heart failure with advanced age [J] . Proc NatlAcad Sci USA, 2003, 100(22): 12 929-12 934.
26. Lutticken C. Wegenk UM, Yuan J, et al . Association of transcriptionfactor APRF and protein kinase JAK-1 with IL-6 signal transducergp130 [J] . Science, 1994, 263(5143): 89-92.
27. Stahl N, Boulton TG, Farruggella T, et al. Association and activation ofJAK-Tyk kinase by CNTF,LIF,OSM, IL-6β-receptor components[J] .Science, 1994, 263(5143): 92-95.
28. Li Y, Cohen R. Caspase inhibitors and myocardial apoptosis [J] . IntAnesthesiol Clin, 2005, 43(2): 77-89.
29. Golstein P. Controlling cell death [J] . Scieneem, 1997, 275 (5303): 1081-1 082.
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31. Long HB, Zhang X, Hou FF, et al. Dynamic changes in plasma nitricoxide and endothelin-1levels in rabbits after endotoxic shock [J] . ChinCrit Care Med, 1998, 10(10): 614 -617.
32.王华东,陆大祥,黄启福,等.心肌JAK/STAT信号通路的研究进展[J].生理科学进展, 2003 , 4 ( 34) : 365-368.
33.李莹洁,柏树令.慢性压力负荷所致心肌肥厚及心衰大鼠左心室肌JAK-STAT的变化[J].中国老年学杂志, 2005, 5 (14) :444-446.
34.樊娟.SOCS和IFN对JAK-STAT活化的影响和意义[J].国际免疫学杂志, 2008, 31 (4) :311-313.
35. O'Sullivan LA, Liongue C, Lewis RS，et al. Cytokine receptorsignaling through the Jak-STAT-Socs pathway in disease [J] . MolImmunol, 2007, 44(10): 2497-2506.研
36. Miettinen KH, Lassus J, Harjola VP, et al. Prognostic role of pro- andanti-inflammatory cytokines and their polymorphisms in acutedecompens -ated heart failure[J] . Eur J Heart Fail, 2008, 10(4):396-403.
37. Suzuki H, SatorR, Sato T, et al. Time-course of changes in the levels ofinterleukin 6 in acutely decompensated heart failure [J] . Int J Cardiol,2005, 100(3): 415-420.
38. Feng QP. Beyond erythropoiesis: the anti-inflammatory effects oferythropoietin [J] . Cardiovasc Res, 2006, 71(4): 615-617.
39.陈茂,范忠才,黄德嘉,等.心脏重量指数评价左心功能不全价值的研究[J].四川医学, 2005, 26 (5): 483-484.
40. Adams KF JR, Fonarow GC, Emerman CL, et al. Characteristics andoutcomes of patients hospitalized for heart failure in the United States:Rationale, design, and preliminary observations from the first 100,000cases in the Acute Decompensated Heart Failure National Registry [J] .Am Heart J, 2005, 149 (2): 209-216.
41. Suzuki H, SatorR, Sato T, et al. Time-course of changes in the levels ofinterleukin 6 in acutely decompensated heart failure [J] . Int J Cardiol,2005, 100(3): 415-420.
42. Palazzuoli A, Silverberg DS, CalabròA, et al. Beta-erythropoietineffects on ventricular remodeling, left and right systolic function,pulmonary pressure, and hospitalizations in patients affected with heartfailure and anemia [J] . J Cardiovasc Pharmacol, 2009, 53(6): 462-467.
43. Ogino A, Takemura G, Kawasaki M, etal. Erythropoietin receptorsignaling mitigates renal dysfunction-associated heart failure bymechanisms unrelated to relief of anemia[J] . J Am Coll Cardiol, 2010,56(23): 1949-1959.
44. Broxmeyer HE. Erythropoietin Surprises: An Immune Saga [J] .Immunity, 2011, 34(1): 6-7.
45. Nairz M, Schroll A, Moschen AR, et al.Erythropoietin ContrastinglyAffects Bacterial Infection and Experimental Colitis by InhibitingNuclear Factor- B-Inducible Immune Pathways[J] . Immunity, 2011,34, (1):61-74.
46. Aspromonte N, Ceci V, Chiera A，et al. Rapid brain natriuretic peptidetest and Doppler echocardiography for early diagnosis of mild heartfailure [J] . Clin Chem, 2006, 52(10): 1 802-1 808.
47. Li L, Takemura G, Li Y, et al. Preventive effect of erythropoietin oncardiac dysfunction in doxorubicin-induced cardiomyopathy [J] .Circulation, 2006, 113(4): 535-543.
48. Wincewicz A, Sulkowska M, Koda M, et al .STAT3, HIF-1alpha, EPOand EPOR signaling proteins in human primary ductal breast cancers[J] . Folia Histochem Cytobiol. 2007, 45(2): 81-86.
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