The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury
The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury
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DOI：
10.1161/01.res.0000202805.73038.48
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发表时间：
2006-02-17
影响因子：
20.1
通讯作者：
Wollert, KC
中科院分区：
文献类型：
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作者：
Kempf, T;Eden, M;Wollert, KC
来自妇女健康研究的数据显示，血清生长分化因子-15（GDF-15）水平是转化生长因子-β超家族的一个远亲，是心血管不良事件的独立风险指标。然而，GDF-15在心血管系统中的细胞来源、上游调节因子和功能作用尚未阐明。我们已经确定了GDF-15的cDNA表达阵列分析作为一个基因，是强烈上调亚硝化应激培养心肌细胞分离1至3天的大鼠。GDF-15 mRNA和前肽的表达水平也诱导心肌细胞进行模拟缺血/再灌注（I/R）通过NO-过氧亚硝酸盐依赖的信号通路。GDF-15被主动分泌到培养上清中，表明其在I/R期间可能发挥自分泌/旁分泌作用。为了探索这些发现的体内相关性，对小鼠进行短暂或永久冠状动脉结扎。心肌GDF-15 mRNA和前肽丰度在缺血损伤后的危险区域迅速增加。类似地，急性心肌梗死患者的心肌GDF-15前肽表达水平增强。如免疫组织化学所示，缺血区域中的心肌细胞对梗塞的人心脏中GDF-15的诱导有显著贡献。为了描述GDF-15在I/R期间的功能，对GDF-15基因靶向的小鼠进行短暂的冠状动脉结扎1小时，然后再灌注24小时。GDF-15缺陷小鼠与野生型同窝仔相比，I/R后梗死边缘区的梗死面积更大，心肌细胞凋亡更多，表明内源性GDF-15限制了体内心肌组织损伤。此外，如组蛋白ELISA、TUNEL/Hoechst染色和膜联蛋白V/碘化丙啶荧光激活细胞分选（FACS）分析所示，用重组GDF-15处理保护培养的心肌细胞在模拟I/R期间免于凋亡。从机制上讲，GDF-15在培养的心肌细胞中的促存活作用被磷酸肌醇3-OH激酶抑制剂和显性阴性Akt 1（K179 M突变）的腺病毒表达所消除。总之，我们的研究将心脏中GDF-15的诱导确定为保护I/R损伤的新防御机制。
Data from the Women's Health Study show that serum levels of growth-differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-beta superfamily, are an independent risk indicator for adverse cardiovascular events. However, the cellular sources, upstream regulators, and functional effects of GDF-15 in the cardiovascular system have not been elucidated. We have identified GDF-15 by cDNA expression array analysis as a gene that is strongly upregulated by nitrosative stress in cultured cardiomyocytes isolated from 1- to 3-day-old rats. GDF-15 mRNA and pro-peptide expression levels were also induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO-peroxynitrite-dependent signaling pathways. GDF-15 was actively secreted into the culture supernatant, suggesting that it might exert autocrine/paracrine effects during I/R. To explore the in vivo relevance of these findings, mice were subjected to transient or permanent coronary artery ligation. Myocardial GDF-15 mRNA and pro-peptide abundance rapidly increased in the area-at-risk after ischemic injury. Similarly, patients with an acute myocardial infarction had enhanced myocardial GDF-15 pro-peptide expression levels. As shown by immunohistochemistry, cardiomyocytes in the ischemic area contributed significantly to the induction of GDF-15 in the infarcted human heart. To delineate the function of GDF-15 during I/R, Gdf-15 gene-targeted mice were subjected to transient coronary artery ligation for 1 hour followed by reperfusion for 24 hours. Gdf-15-deficient mice developed greater infarct sizes and displayed more cardiomyocyte apoptosis in the infarct border zone after I/R compared with wild-type littermates, indicating that endogenous GDF-15 limits myocardial tissue damage in vivo. Moreover, treatment with recombinant GDF-15 protected cultured cardiomyocytes from apoptosis during simulated I/R as shown by histone ELISA, TUNEL/Hoechst staining, and annexin V/propidium iodide fluorescence-activated cell sorting (FACS) analysis. Mechanistically, the prosurvival effects of GDF-15 in cultured cardiomyocytes were abolished by phosphoinositide 3-OH kinase inhibitors and adenoviral expression of dominant-negative Akt1 (K179M mutation). In conclusion, our study identifies induction of GDF-15 in the heart as a novel defense mechanism that protects from I/R injury.