Growth Differentiation Factor 15 Acts Anti-Apoptotic and Pro-Hypertrophic in Adult Cardiomyocytes
Growth Differentiation Factor 15 Acts Anti-Apoptotic and Pro-Hypertrophic in Adult Cardiomyocytes
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DOI：
10.1002/jcp.22102
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发表时间：
2010-07-01
影响因子：
5.6
通讯作者：
Euler, G.
中科院分区：
文献类型：
--
作者：
Heger, J.;Schiegnitz, E.;Euler, G.
生长分化因子15 （GDF15）在心力衰竭的发展过程中被诱导，并可能影响心脏重塑的不同过程。虽然其在缺血-再灌注条件下的抗凋亡作用已被证明，但尚不清楚这是否适用于其他凋亡刺激的广泛保护作用。此外，对心脏肥厚的影响仍不清楚。因此，我们研究了GDF15对心室心肌细胞肥大和凋亡的诱导作用。GDF15 （3ng /ml）促进心肌细胞肥厚生长，细胞大小增加27 +/- 5%，蛋白质合成率增加47 +/- 15%。此外，研究发现smad结合亲和力呈时间和剂量依赖性增加，R-SMAD的磷酸化也增强。通过smad -诱导剂寡核苷酸转化心肌细胞抑制smad，可消除肥厚生长效应。PI3K特异性抑制剂（10 μ M LY290042或10 μ M wortmannin）或ERK特异性抑制剂（10 μ M PD98059）也能阻断gdf15诱导的肥大和SMAD激活。100 nM血管紧张素II、1 ng/ml TGF β(1)或no供体SNAP （100 μ M）三种不同药物诱导的细胞凋亡被添加GDF15 （3 ng/ml）阻断。用smad -诱骗寡核苷酸转化心肌细胞清除smad，可消除GDF15的抗凋亡作用。综上所述，GDF15可保护心室心肌细胞免受不同凋亡刺激并促进肥厚生长。因此，肥大信号是通过激酶P13K和ERK以及转录因子R-SMAD i介导的。因此，GDF15可能通过两种不同的机制影响心脏重塑，即凋亡保护和诱导肥大。j .细胞。中国生物医学工程学报，2009,31(2):557 - 557。(C) 2010 Wiley-Liss, Inc。
Growth differentiation factor 15 (GDF15) is induced during heart failure development, and may influence different processes in cardiac remodeling. While its anti-apoptotic action under conditions of ischemia-reperfusion have been shown, it remained unclear if this is a broadly protective effect applicable to other apoptotic stimuli. Furthermore, effects on cardiac hypertrophy remained obscure. Therefore, we investigated the effects of GDF15 on induction of hypertrophy and apoptosis in ventricular cardiomyocytes. GDF15 (3 ng/ml) enhanced hypertrophic growth of cardiomyocytes as determined by an increase in cell size by 27 +/- 5% and rate of protein synthesis by 47 +/- 15%. In addition, a time and dose-dependent increase in SMAD-binding affinity was found, as well as enhanced phosphorylation of R-SMAD I. Inhibition of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the hypertrophic growth effect. Specific inhibitors of PI3K (10 mu M LY290042 or 10 nM wortmannin) or ERK (10 mu M PD98059) also blocked GDF15-induced hypertrophy and SMAD activation. Apoptosis induction by three different agents, 100 nM angiotensin II, 1 ng/ml TGF beta(1), or the NO-donor SNAP (100 mu M) was blocked by addition of GDF15 (3 ng/ml). Scavenging of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the anti-apoptotic effect of GDF15. In conclusion, GDF15 protects ventricular cardiomyocytes against different apoptotic stimuli and enhances hypertrophic growth. Hypertrophic signaling is thereby mediated via the kinases P13K and ERK and the transcription factor R-SMAD I. Thus, GDF15 may influence cardiac remodeling via two different mechanisms, apoptosis protection and induction of hypertrophy. J. Cell. Physiol. 224: 120-126, 2010. (C) 2010 Wiley-Liss, Inc.