缺氧通过HIF-1α诱导心肌细胞分泌TNF-α的机制研究
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摘要
第一部分缺氧通过HIF-1α诱导心肌细胞分泌细胞因子TNF-α
目的：越来越多证据显示急性心肌梗死中过量肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)表达对心肌细胞不利。心肌缺血时,TNF-α主要来源于巨噬细胞。随着缺血状态的持续,心肌细胞开始分泌TNF-α.我们探讨缺氧是否通过缺氧诱导因子-1α(hypoxia inducible factor 1α, HIF-1α)诱导心肌细胞自分泌细胞因子TNF-α。
方法和结果：分离新生大鼠乳鼠心肌细胞,分别给予氧浓度1%缺氧刺激5分钟,15分钟,30分钟,1小时,2小时,4小时,6小时,12小时,24小时。western blot检测细胞HIF-1α蛋白表达水平；免疫荧光检测HIF-1α蛋白表达以及入核情况；实时定量RT-PCR检测TNF-a mRNA表达水平；ELISA检测TNF-α蛋白表达分泌。结果显示TNF-αmRNA从1小时开始表达上调,与空白组相比增加至1.99±0.27倍(p<0.01),12小时及24小时达峰值,分别为4.06±0.84倍和4.09±0.81倍(p<0.01)。TNF-α蛋白分泌表达在6小时可检测到,12小时达峰值为48.12±11.52pg/ml(p＜0.01)。缺氧对HIF-1αmRNA水平无影响,HIF-1α蛋白缺氧30分钟表达明显,1小时达峰值。免疫荧光染色提示缺氧15分钟HIF-1α蛋白开始表达且向核内聚积。核转染法进行心肌细胞HIF-1αRNA干扰,发现siRNA显著抑制HIF-1αmRNA水平的同时,抑制缺氧12小时后TNF-αmRNA水平上调(3.75±0.45 fold vs 1.38±0.76 fold,p<0.01)。HIF-1α抑制剂2-甲氧雌二醇(2-methoxyestradiol,2ME2)能有效抑制缺氧刺激后HIF-1α蛋白表达,也能抑制缺氧12小时后TNF-αmRNA水平上调(2.82±0.41 fold vs 1.31±0.37fold,p<0.01)以及蛋白分泌(48.12±11.52pg/ml vs 23.22±2.62,p<0.05)。
结论：缺氧能诱导离体心肌细胞分泌细胞因子TNF-α, HIF-1α在缺氧诱导心肌细胞自分泌TNF-α过程中发挥重要调节作用。
第二部分缺氧及模拟缺氧状态下HIF-1α对TNF-α直接启动作用的研究
目的：探讨缺氧诱导因子-1α(hypoxia inducible factor 1α, HIF-1α)对于肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)是否有直接启动作用。
方法和结果：培养HEK293细胞和HepG2细胞,给予氧浓度1%缺氧刺激及氯化钻模拟缺氧刺激后,western blot检测胞核HIF-1α蛋白表达水平,实时定量RT-PCR检测TNF-αmRNA表达水平。结果显示缺氧6小时及氯化钻刺激3小时可明显观察到HIF-1α蛋白在胞核内稳定表达,缺氧12h及氯化钴刺激12h后与空白组相比TNF-αmRNA水平明显上升。HIF-1α抑制剂2-甲氧雌二醇(2-methoxyestradiol,2ME2)能有效抑制氯化钻模拟缺氧刺激后HIF-1α在核内聚积,也能抑制氯化钴模拟缺氧刺激后TNF-αmRNA水平上调。分析TNF-α转录起始位点上游5000bp的启动子区域,发现七个可能缺氧反应元件(hypoxia response elements, HREs)。5'端续减法构建8个不同长度的报告基因质粒,瞬时转染入HEK293细胞和HepG2细胞,予氧浓度1%缺氧刺激24小时后双荧光素酶报告基因法检测启动子活性。结果显示TNF-α转录起始位点上游-1470bp处可能为缺氧诱导TNF-α启动子的功能位点。
结论：我们发现TNF-α是一种缺氧诱导表达基因,它的转录调节可能通过HIF-1与位于TNF-α启动子-1470bp处HRE位点相互作用发挥效应。
PartⅠ
Hypoxia induced autocrine of TNF-a by hypoxia-inducible factor-la in cardiomyocytes
Aims:Growing evidence indicates that excessive tumor necrosis factor-a (TNF-a) expression are detrimental to cardiomyocytes in acute myocardial infarction. During myocardial ischemia, TNF-a is mainly released from macrophages, with persisent ischemia, TNF-a can originate from cardiomyocytes. We hypothesized the direct effects of hypoxia on TNF-a expression by hypoxia-inducible factor-la (HIF-la) in cardiomyocytes.
Methods and results:Neonatal rat cardiomyocytes were exposed in a hypoxic incubator containing 1% oxygen for 5 minutes,15 minutes,30 minutes,1 hour,2 hours,4 hours,6 hours,12 hours and 24 hours. TNF-a mRNA increased slightly as early as 30 minutes (1.99±0.27 fold compared to control group,p<0.01), peaked at 12 hours (4.06±0.84 fold,p＜0.01) and 24 hours (4.09±0.81 fold,p＜0.01). TNF-a secretion became detectable as early as 6 hours and peaked at 12 hours (48.12±11.52 pg/ml) by ELISA. Hypoxia had no effect on HIF-la mRNA change (p>0.05) by real-time RT-PCR assay. Protein expression of HIF-1αwas detectable at 30 minutes and peaked at 1 hour by western blot. Immunofluorescent staining showed HIF-1αwas obviously observed as early as 15 minutes, meanwhile, it had the trends to translocate into cell nucleus. HIF-1αmRNA was downregulated effectively by siRNA through Nucleofection, meanwhile, TNF-αmRNA elevation after 12-hour hypoxia was obviously inhibited (3.75±0.45 fold vs 1.38±0.76 fold, p<0.01). Expression of HIF-la was inhibited effectively by 2-Methoxyestradiol (2ME2) after hypoxia, and 2ME2 also decreased TNF-αmRNA after 12-hour hypoxia (2.82±0.41 fold vs 1.31±0.37 fold,p＜0.01) and TNF-a secretion (48.12±11.52pg/ml vs 23.22±2.62, p＜0.05).
Conclusions:Hypoxia induces autocrine of TNF-αby cardiomyocytes in vitro. HIF-1αplays an important role in hypoxia mediated TNF-αexpression and secretion in cardiomyocytes.
PartⅡ
Regulation of TNF-a promoter by hypoxia inducible factor-la under hypoxia or CoCl2 mimicked hypoxia
Aims:We investigated the direct effects of hypoxia on tumor necrosis factor-a (TNF-α) expression, and the role of hypoxia inducible factor-la (HIF-la) in TNF-a regulation.
Methods and results:HEK293 and HepG2 cells were exposed in a hypoxia (1% O2) chamber or treated with CoCl2 to mimic hypoxia. HIF-la nuclear protein expression was detected by western blot, TNF-a mRNA levels were assayed by real time PCR. Significant up-regulation of HIF-la nuclear protein could be seen in both cell lines after 6-hour hypoxia and 3-hour CoCl2 mimic hypoxia stimulation. Obvious up-regulation of TNF-αmRNA levels was observed after 12-hour hypoxia and 12-hour CoCl2 mimic hypoxia. Inhibition of HIF-1αby 2-methoxyestradiol (2ME2) inhibited CoCl2 induced HIF-1αnuclear protein accumulation and TNF-a mRNA elevation. We found seven possible hypoxia response elements (HREs) at regions of 5'to the proximal 5000-bp fragment of the TNF-αpromoter relative to the transcription start site. Eight reporter gene plasmids were constructed after promoter truncation analysis, and then transiently transfected into HEK293 and HepG2 cells. Promoter activity was detected by dual-luciferase reporter assay after 24-hour hypoixa treatment. The results showed HIF consensus binding sites spanning bp-1470 relative to the transcription start site were functional for TNF-a promoter activity induction by hypoxia.
Conclusions:We demonstrate that TNF-a is a hypoxia-inducible gene, whose transcription is stimulated through HIF-1αinteraction with HRE sites located at-1470 of the TNF-a promoter.
目的：越来越多证据显示急性心肌梗死中过量肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)表达对心肌细胞不利。心肌缺血时,TNF-α主要来源于巨噬细胞。随着缺血状态的持续,心肌细胞开始分泌TNF-α.我们探讨缺氧是否通过缺氧诱导因子-1α(hypoxia inducible factor 1α, HIF-1α)诱导心肌细胞自分泌细胞因子TNF-α。
方法和结果：分离新生大鼠乳鼠心肌细胞,分别给予氧浓度1%缺氧刺激5分钟,15分钟,30分钟,1小时,2小时,4小时,6小时,12小时,24小时。western blot检测细胞HIF-1α蛋白表达水平；免疫荧光检测HIF-1α蛋白表达以及入核情况；实时定量RT-PCR检测TNF-a mRNA表达水平；ELISA检测TNF-α蛋白表达分泌。结果显示TNF-αmRNA从1小时开始表达上调,与空白组相比增加至1.99±0.27倍(p<0.01),12小时及24小时达峰值,分别为4.06±0.84倍和4.09±0.81倍(p<0.01)。TNF-α蛋白分泌表达在6小时可检测到,12小时达峰值为48.12±11.52pg/ml(p＜0.01)。缺氧对HIF-1αmRNA水平无影响,HIF-1α蛋白缺氧30分钟表达明显,1小时达峰值。免疫荧光染色提示缺氧15分钟HIF-1α蛋白开始表达且向核内聚积。核转染法进行心肌细胞HIF-1αRNA干扰,发现siRNA显著抑制HIF-1αmRNA水平的同时,抑制缺氧12小时后TNF-αmRNA水平上调(3.75±0.45 fold vs 1.38±0.76 fold,p<0.01)。HIF-1α抑制剂2-甲氧雌二醇(2-methoxyestradiol,2ME2)能有效抑制缺氧刺激后HIF-1α蛋白表达,也能抑制缺氧12小时后TNF-αmRNA水平上调(2.82±0.41 fold vs 1.31±0.37fold,p<0.01)以及蛋白分泌(48.12±11.52pg/ml vs 23.22±2.62,p<0.05)。
结论：缺氧能诱导离体心肌细胞分泌细胞因子TNF-α, HIF-1α在缺氧诱导心肌细胞自分泌TNF-α过程中发挥重要调节作用。
第二部分缺氧及模拟缺氧状态下HIF-1α对TNF-α直接启动作用的研究
目的：探讨缺氧诱导因子-1α(hypoxia inducible factor 1α, HIF-1α)对于肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)是否有直接启动作用。
方法和结果：培养HEK293细胞和HepG2细胞,给予氧浓度1%缺氧刺激及氯化钻模拟缺氧刺激后,western blot检测胞核HIF-1α蛋白表达水平,实时定量RT-PCR检测TNF-αmRNA表达水平。结果显示缺氧6小时及氯化钻刺激3小时可明显观察到HIF-1α蛋白在胞核内稳定表达,缺氧12h及氯化钴刺激12h后与空白组相比TNF-αmRNA水平明显上升。HIF-1α抑制剂2-甲氧雌二醇(2-methoxyestradiol,2ME2)能有效抑制氯化钻模拟缺氧刺激后HIF-1α在核内聚积,也能抑制氯化钴模拟缺氧刺激后TNF-αmRNA水平上调。分析TNF-α转录起始位点上游5000bp的启动子区域,发现七个可能缺氧反应元件(hypoxia response elements, HREs)。5'端续减法构建8个不同长度的报告基因质粒,瞬时转染入HEK293细胞和HepG2细胞,予氧浓度1%缺氧刺激24小时后双荧光素酶报告基因法检测启动子活性。结果显示TNF-α转录起始位点上游-1470bp处可能为缺氧诱导TNF-α启动子的功能位点。
结论：我们发现TNF-α是一种缺氧诱导表达基因,它的转录调节可能通过HIF-1与位于TNF-α启动子-1470bp处HRE位点相互作用发挥效应。
PartⅠ
Hypoxia induced autocrine of TNF-a by hypoxia-inducible factor-la in cardiomyocytes
Aims:Growing evidence indicates that excessive tumor necrosis factor-a (TNF-a) expression are detrimental to cardiomyocytes in acute myocardial infarction. During myocardial ischemia, TNF-a is mainly released from macrophages, with persisent ischemia, TNF-a can originate from cardiomyocytes. We hypothesized the direct effects of hypoxia on TNF-a expression by hypoxia-inducible factor-la (HIF-la) in cardiomyocytes.
Methods and results:Neonatal rat cardiomyocytes were exposed in a hypoxic incubator containing 1% oxygen for 5 minutes,15 minutes,30 minutes,1 hour,2 hours,4 hours,6 hours,12 hours and 24 hours. TNF-a mRNA increased slightly as early as 30 minutes (1.99±0.27 fold compared to control group,p<0.01), peaked at 12 hours (4.06±0.84 fold,p＜0.01) and 24 hours (4.09±0.81 fold,p＜0.01). TNF-a secretion became detectable as early as 6 hours and peaked at 12 hours (48.12±11.52 pg/ml) by ELISA. Hypoxia had no effect on HIF-la mRNA change (p>0.05) by real-time RT-PCR assay. Protein expression of HIF-1αwas detectable at 30 minutes and peaked at 1 hour by western blot. Immunofluorescent staining showed HIF-1αwas obviously observed as early as 15 minutes, meanwhile, it had the trends to translocate into cell nucleus. HIF-1αmRNA was downregulated effectively by siRNA through Nucleofection, meanwhile, TNF-αmRNA elevation after 12-hour hypoxia was obviously inhibited (3.75±0.45 fold vs 1.38±0.76 fold, p<0.01). Expression of HIF-la was inhibited effectively by 2-Methoxyestradiol (2ME2) after hypoxia, and 2ME2 also decreased TNF-αmRNA after 12-hour hypoxia (2.82±0.41 fold vs 1.31±0.37 fold,p＜0.01) and TNF-a secretion (48.12±11.52pg/ml vs 23.22±2.62, p＜0.05).
Conclusions:Hypoxia induces autocrine of TNF-αby cardiomyocytes in vitro. HIF-1αplays an important role in hypoxia mediated TNF-αexpression and secretion in cardiomyocytes.
PartⅡ
Regulation of TNF-a promoter by hypoxia inducible factor-la under hypoxia or CoCl2 mimicked hypoxia
Aims:We investigated the direct effects of hypoxia on tumor necrosis factor-a (TNF-α) expression, and the role of hypoxia inducible factor-la (HIF-la) in TNF-a regulation.
Methods and results:HEK293 and HepG2 cells were exposed in a hypoxia (1% O2) chamber or treated with CoCl2 to mimic hypoxia. HIF-la nuclear protein expression was detected by western blot, TNF-a mRNA levels were assayed by real time PCR. Significant up-regulation of HIF-la nuclear protein could be seen in both cell lines after 6-hour hypoxia and 3-hour CoCl2 mimic hypoxia stimulation. Obvious up-regulation of TNF-αmRNA levels was observed after 12-hour hypoxia and 12-hour CoCl2 mimic hypoxia. Inhibition of HIF-1αby 2-methoxyestradiol (2ME2) inhibited CoCl2 induced HIF-1αnuclear protein accumulation and TNF-a mRNA elevation. We found seven possible hypoxia response elements (HREs) at regions of 5'to the proximal 5000-bp fragment of the TNF-αpromoter relative to the transcription start site. Eight reporter gene plasmids were constructed after promoter truncation analysis, and then transiently transfected into HEK293 and HepG2 cells. Promoter activity was detected by dual-luciferase reporter assay after 24-hour hypoixa treatment. The results showed HIF consensus binding sites spanning bp-1470 relative to the transcription start site were functional for TNF-a promoter activity induction by hypoxia.
Conclusions:We demonstrate that TNF-a is a hypoxia-inducible gene, whose transcription is stimulated through HIF-1αinteraction with HRE sites located at-1470 of the TNF-a promoter.
引文
1 中华医学会心血管病学会.慢性心力衰竭诊断治疗指南.中华心血管病杂志,2007：35：1076-95
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10 Irwin M, Mak S, Mann D, etc. Tissue expression and immunolocalization of tumour necrosis factor-alpha in post infarction-dysfunctional myocardium. Circulation 1999; 99:1492-98
11程翔,廖玉华,李彬等。早期美托洛尔治疗改善急性心肌梗死大鼠心肌炎症 因子表达和心功能。中华心血管病杂志,2005；33：448-52
12 Murray DR, Prabhu SD, Chandrasekar B. Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation 2000; 101: 2338-41
13 Nian M, Lee P, Khaper N, etc. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 2004; 94:1543-53
14 Ono K, Matsumori A, Shioi T, etc. Cytokine gene expression after myocardial infarction in rat hearts:possible implication in left ventricular remodeling. Circulation 1998; 98:149-56
15 Yamaoka M, Yamaguchi S, Okuyama M, etc. Anti-inflammatory cytokine profile in human heart failure:behavior of interleukine-10 in association with tumor necrosis factor-alpha. Jpn Circ J 1999; 63:951-95
16 Li H, Ko HP, Whitlock JP. Induction of phosphoglycerate kinase 1 gene expression by hypoxia. Roles of ARNT and HIF1alpha. J Biol Chem 1996; 271: 21262-7
17 Huang J, Zhao Q, Mooney SM, etc. Sequence determinants in hypoxia inducible factor-1 for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem 2002; 277:39792-800
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22 Chen WY, Chang MS. IL-20 is regulated by hypoxia-inducible factor and up-regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke. J Immunol 2009; 182:5003-12
23 Hellwig-Burgel T, Rutkowski K, Metzen E, etc. Interleukin-1β and tumor necrosis factor-a stimulate DNA binding of hypoxia-inducible factor-1. Blood 1999; 94:1561-7
24 Scharte M, Han X, Bertges DJ, etc. Cytokines induce HIF-1 DNA binding and the expression of HIF-1-dependent genes in cultured rat enterocytes. Am. J. Physiol. Gastrointest. Liver Physiol 2003; 284, G373-84
1 中华医学会心血管病学会.慢性心力衰竭诊断治疗指南.中华心血管病杂志,2007：35：1076-95
2 Liao YH, Cheng X. Autoimmunity in myocardial infarction. International Journal of Cardiology 2006; 112:21-6
3 Kapadia SR, Oral H, Lee J, etc. Hemodynamic regulation of tumor necrosis factor-a gene and protein expression in adult feline myocardium. Circ Res 1997; 81:187-195
4 Kapadia S, Lee J, Torre-Amione G, etc. Tumor necrosis factor-a gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 1995; 96:1042-52
5 Irwin M, Mak S, Mann D, etc. Tissue expression and immunolocalization of tumour necrosis factor-alpha in post infarction-dysfunctional myocardium. Circulation 1999; 99:1492-98
6 程翔,廖玉华,李彬,等。早期美托洛尔治疗改善急性心肌梗死大鼠心肌炎症因子表达和心功能。中华心血管病杂志,2005；33：448-52
7 Murray DR, Prabhu SD, Chandrasekar B. Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation 2000; 101: 2338-41
8 Nian M, Lee P, Khaper N, etc. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 2004; 94:1543-53
9 Ono K, Matsumori A, Shioi T, etc. Cytokine gene expression after myocardial infarction in rat hearts:possible implication in left ventricular remodeling. Circulation 1998; 98:149-56
10 Yamaoka M, Yamaguchi S, Okuyama M, etc. Anti-inflammatory cytokine profile in human heart failure:behavior of interleukine-10 in association with tumor necrosis factor-alpha. Jpn Circ J 1999; 63:951-95
11 Semenza GL, Nejfelt MK, Chi SM, etc. Hypoxia-inducible nuclear factors bind to an enhancer element located 3'to the human erythropoietin gene. Proc Natl Acad Sci USA 1991; 88:5680-4
12 Hellwig-Burgel T, Rutkowski K, Metzen E, etc. Interleukin-1β and tumor necrosis factor-a stimulate DNA binding of hypoxia-inducible factor-1. Blood 1999;94:1561-7
13 Scharte M, Han X, Bertges DJ, etc. Cytokines induce HIF-1 DNA binding and the expression of HIF-1-dependent genes in cultured rat enterocytes. Am. J. Physiol. Gastrointest. Liver Physiol 2003; 284, G373-84
14 Paul S, Shoshana S. Differentiation of Rat Myocytes in Single Cell Cultures with and without Proliferating Nonmyocardial Cells. Circ Res 1982; 50:101-16
15 Von HR, Li PF, Dietz R. Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 1999; 99:2934-41
16 Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270:1230-7
17 Wang GL, Jiang BH, Rue EA, etc. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92:5510-4
18 Jiang BH, Rue E, Wang GL, etc. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 1996; 271:17771-8
19 Heidbreder M, Frohlich F, Johren O. Hypoxia rapidly activates HIF-3α mRNA expression. FASEB J 2003; 17:1541-3
20 Maxwell PH, Wiesener MS, Chang GW, etc. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399:271
21 Huang J, Zhao Q, Mooney SM, etc. Sequence determinants in hypoxia inducible factor-1 for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem 2002; 277:39792-800
22 Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol 1993; 9:317-43
23 Sack MN, Smith RM, Opie LH. Tumor necrosis factor in myocardial hypertrophy and ischaemia-an anti-apoptotic perspective. Cardiovasc Res 2000; 45:688-95.
24 Mann DL. The effect of tumor necrosis factor-a on cardiac structure and function: a tale of two cytokines. J Card Fail 1996; 2:S165-72
25 Sack M. Tumor necrosis factor-a in cardiovascular biology and the potential role for anti-tumor necrosis factor-a therapy in heart disease. Pharmacol Ther 2002; 94:123-35
26 Peyssonnaux C, Datta V, Cramer T, etc. HIF-1α expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005; 115:1806-15
27 Peyssonnaux C, Cejudo-Martin P, Doedens A, etc. Cutting edge:Essential role of hypoxia inducible factor-la in development of lipopolysaccharide-induced sepsis. J Immunol 2007; 178:7516-9
1 Taylor CT, Colgan SP. Hypoxia and gastrointestinal disease. J Mol Med 2007; 85: 1295-300
2 Karhausen J, Haase VH, Colgan SP. Inflammatory hypoxia:Role for hypoxia-inducible factor. Cell Cycle 2005; 4:256-8
3 Hatoum OA, Miura H, Binion DG. The vascular contribution in the pathogenesis of inflammatory bowel disease. Am J Physiol Heart Circ Physiol 2003; 285: 1791-6
4 Zinkernagel AS, Johnson RL, Nizit V. Hypoxia inducible factor (HIF) function in innate immunity and infection. J MolMed 2007; 85:1339-46
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1 中华医学会心血管病学会.慢性心力衰竭诊断治疗指南.中华心血管病杂志,2007：35：1076-95
2 Liao YH, Cheng X. Autoimmunity in myocardial infarction. International Journal of Cardiology 2006; 112:21-6
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5 Irwin M, Mak S, Mann D, etc. Tissue expression and immunolocalization of tumour necrosis factor-alpha in post infarction-dysfunctional myocardium. Circulation 1999; 99:1492-98
6 程翔,廖玉华,李彬,等。早期美托洛尔治疗改善急性心肌梗死大鼠心肌炎症因子表达和心功能。中华心血管病杂志,2005；33：448-52
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