GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity.
GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity.
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GRK5介导的病理心肥大的加剧涉及促进核NFAT活性。
DOI：
10.1161/circresaha.116.304475
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发表时间：
2014-12-05
影响因子：
20.1
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
Hullmann JE;Grisanti LA;Makarewich CA;Gao E;Gold JI;Chuprun JK;Tilley DG;Houser SR;Koch WJ
作用于心肌细胞的 G 蛋白偶联受体 (GPCR) 激酶 (GRK) 调节控制心脏功能的重要信号事件。 GRK2 和 GRK5 是心脏中表达的主要 GRK，已被证明在人类心肌衰竭中表达上调。虽然 GRK 的典型作用是通过磷酸化使 GPCR 脱敏，但已证明，与 GRK2 不同，GRK5 可以驻留在肌细胞的细胞核中，并发挥不依赖于 GPCR 的作用，从而促进适应不良的心脏肥大和心力衰竭 (HF)。探讨GRK5作用于心肌细胞核参与病理性心脏肥大的新机制。在这项研究中，我们发现GRK5介导的病理性心脏肥大涉及激活T细胞核因子（NFAT）的激活，因为GRK5导致NFAT介导的肥厚基因转录增强。心肌细胞特异性 GRK5 过表达的转基因小鼠在基础上和在包括横主动脉缩窄 (TAC) 和去氧肾上腺素治疗在内的肥大刺激后激活小鼠体内的 NFAT 报告基因。与此互补的是，GRK5 缺失小鼠在 TAC 后表现出较低的 NFAT 转录活性。此外，心脏中 NFATc3 表达的丧失可以保护 GRK5 过度表达的转基因小鼠免受 TAC 后出现的过度肥大和早期进展为 HF 的影响。分子研究表明，GRK5 与 NFAT 协同作用，通过 GRK5 直接结合 DNA 而不发生磷酸化事件的能力，增加细胞核中肥大基因的转录。 GRK5 以不依赖于激酶的方式发挥作用，是 NFAT 活性的促进剂，也是负责病理性肥大基因转录的 DNA 结合复合物的一部分。
G protein-coupled receptor (GPCR) kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be up-regulated in failing human myocardium. While the canonical role of GRKs is to desensitize GPCRs via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert GPCR-independent effects that promote maladaptive cardiac hypertrophy and heart failure (HF). To explore novel mechanisms by which GRK5 acting in the nucleus of cardiomyocytes participates in pathological cardiac hypertrophy. In this study, we have found that GRK5-mediated pathological cardiac hypertrophy involves the activation of nuclear factor of activated T-cells (NFAT) as GRK5 causes enhancement of NFAT-mediated hypertrophic gene transcription. Transgenic mice with cardiomyocyte-specific GRK5 overexpression activate an NFAT-reporter in mice basally and after hypertrophic stimuli including transverse aortic constriction (TAC) and phenylephrine treatment. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after TAC. Further, loss of NFATc3 expression in the heart protected GRK5 overexpressing transgenic mice from the exaggerated hypertrophy and early progression to HF seen after TAC. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus via GRK5’s ability to bind DNA directly without a phosphorylation event. GRK5, acting in a kinase-independent manner, is a facilitator of NFAT activity and part of a DNA binding complex responsible for pathological hypertrophic gene transcription.