The Amino-Terminal Domain of GRK5 Inhibits Cardiac Hypertrophy through the Regulation of Calcium-Calmodulin Dependent Transcription Factors.
The Amino-Terminal Domain of GRK5 Inhibits Cardiac Hypertrophy through the Regulation of Calcium-Calmodulin Dependent Transcription Factors.
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DOI：
10.3390/ijms19030861
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发表时间：
2018-03-15
影响因子：
5.6
通讯作者：
Iaccarino G
中科院分区：
文献类型：
--
作者：
Sorriento D;Santulli G;Ciccarelli M;Maione AS;Illario M;Trimarco B;Iaccarino G
我们最近证实，G蛋白偶联受体激酶（GRK）5型氨基端结构域（GRK 5-NT）抑制心肌细胞NF κ B活性，从而显著改善LVH。由于GRK5-NT已知结合钙调素，本研究旨在评估GRK5-NT在钙-钙调素依赖性转录因子调节中的功能作用。我们发现GRK5-NT在心肌细胞中的过表达显著降低了苯肾上腺素（PE）对NFAT及其辅因子加塔-4的激活和核转位。这些结果在自发性高血压大鼠（SHR）体内得到了证实，其中心肌内腺病毒介导的GRK5-NT基因转移通过调节NFAT和加塔-4活性降低了室壁厚度和心室质量。为了在体外进一步验证钙调蛋白在连接GRK5-NT与NFAT/加塔-4途径中的作用，我们检测了不能结合钙调蛋白的GRK5突变体（GRK5-NTPB）的作用。当与GRK5-NT相比时，GRK5-NTPB不改变PE诱导的NFAT和加塔-4活化。总之，本研究确定了GRK5-NT在抑制LVH中的双重作用，其基于通过不同机制调节多种转录因子，并提出GRK5的氨基末端序列作为用于治疗目的的有用原型。
We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK) type 5, (GRK5-NT) inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE). These results were confirmed in vivo in spontaneously hypertensive rats (SHR), in which intramyocardial adenovirus-mediated gene transfer of GRK5-NT reduced both wall thickness and ventricular mass by modulating NFAT and GATA-4 activity. To further verify in vitro the contribution of calmodulin in linking GRK5-NT to the NFAT/GATA-4 pathway, we examined the effects of a mutant of GRK5 (GRK5-NTPB), which is not able to bind calmodulin. When compared to GRK5-NT, GRK5-NTPB did not modify PE-induced NFAT and GATA-4 activation. In conclusion, this study identifies a double effect of GRK5-NT in the inhibition of LVH that is based on the regulation of multiple transcription factors through means of different mechanisms and proposes the amino-terminal sequence of GRK5 as a useful prototype for therapeutic purposes.
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DOI：
10.1291/hypres.22.1
发表时间：
1999-03-01
期刊：
HYPERTENSION RESEARCH-CLINICAL AND EXPERIMENTAL
影响因子：
--
作者：
Devereux, RB;Roman, MJ
通讯作者：
Roman, MJ
GRK5介导的病理心肥大的加剧涉及促进核NFAT活性。
影响因子：
20.1
作者：
Hullmann JE;Grisanti LA;Makarewich CA;Gao E;Gold JI;Chuprun JK;Tilley DG;Houser SR;Koch WJ
通讯作者：
Koch WJ
影响因子：
5.3
作者：
Johnson, LR;Scott, MGH;Pitcher, JA
通讯作者：
Pitcher, JA
影响因子：
5.3
作者：
Liang, QR;Wiese, RJ;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
20.1
作者：
Liu Q;Chen Y;Auger-Messier M;Molkentin JD
通讯作者：
Molkentin JD