A novel role of G protein-coupled receptor kinase 5 in urotensin II-stimulated cellular hypertrophy in H9c2UT cells
A novel role of G protein-coupled receptor kinase 5 in urotensin II-stimulated cellular hypertrophy in H9c2UT cells
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DOI：
10.1007/s11010-016-2814-y
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发表时间：
2016-11-01
影响因子：
4.3
通讯作者：
Oh, Kwang-Seok
中科院分区：
文献类型：
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作者：
Park, Cheon Ho;Lee, Ju Hee;Oh, Kwang-Seok
尾加压素 II (UII) 是一种神经激素，可诱导心脏肥大，可能参与心脏重塑和心力衰竭的发病机制。肥大与组蛋白脱乙酰酶 5 (HDAC5) 磷酸化和核因子 kappa B (NF-kappa B) 易位有关，这两者主要由 G 蛋白偶联受体激酶 5 (GRK5) 介导。在本研究中，我们发现UII快速而强烈地刺激过表达尾加压素II受体(H9c2(UT))的H9c2细胞中HDAC5的核输出和NF-κB的核输入。因此，我们假设 GRK5 及其信号通路可能在 UII 介导的细胞肥大中发挥作用。用GRK5小发夹RNA干扰重组慢病毒转导H9c2(UT)细胞，导致GRK5下调。在UII刺激下，H9c2(UT)细胞中GRK5水平降低导致UII介导的HDAC5磷酸化受到抑制并激活NF-kappa B信号通路。相比之下，UII 介导的 ERK1/2 和 GSK3 α/β 激活不受 GRK5 下调的影响。在细胞肥大测定中，GRK5 的下调显着抑制 UII 介导的 H9c2(UT) 细胞肥大。此外，在 H9c2(UT) 细胞和新生儿心肌细胞中，氨来呫诺 (amlexanox)（一种选择性 GRK5 抑制剂）可抑制 UII 介导的细胞肥大。我们的结果表明，GRK5 可能至少部分通过 ERK1/2 和 GSK3 α/β 独立途径激活 NF-κ B 和 HDAC5，参与 UII 介导的肥大反应。
Urotensin II (UII) is a neural hormone that induces cardiac hypertrophy and may be involved in the pathogenesis of cardiac remodeling and heart failure. Hypertrophy has been linked to histone deacetylase 5 (HDAC5) phosphorylation and nuclear factor kappa B (NF-kappa B) translocation, both of which are predominantly mediated by G protein-coupled receptor kinase 5 (GRK5). In the present study, we found that UII rapidly and strongly stimulated nuclear export of HDAC5 and nuclear import of NF-kappa B in H9c2 cells overexpressing the urotensin II receptor (H9c2(UT)). Hence, we hypothesized that GRK5 and its signaling pathway may play a role in UII-mediated cellular hypertrophy. H9c2(UT) cells were transduced with a GRK5 small hairpin RNA interference recombinant lentivirus, resulting in the down-regulation of GRK5. Under UII stimulation, reduced levels of GRK5 in H9c2(UT) cells led to suppression of UII-mediated HDAC5 phosphorylation and activation of the NF-kappa B signaling pathway. In contrast, UII-mediated activations of ERK1/2 and GSK3 alpha/beta were not affected by down-regulation of GRK5. In a cellular hypertrophy assay, down-regulation of GRK5 significantly suppressed UII-mediated hypertrophy of H9c2(UT) cells. Furthermore, UII-mediated cellular hypertrophy was inhibited by amlexanox, a selective GRK5 inhibitor, in H9c2(UT) cells and neonatal cardiomyocytes. Our results suggest that GRK5 may be involved in a UII-mediated hypertrophic response via activation of NF-kappa B and HDAC5 at least in part by ERK1/2 and GSK3 alpha/beta-independent pathways.