The poly(ADP-ribosyl)ation of FoxO3 mediated by PARP1 participates in isoproterenol-induced cardiac hypertrophy
The poly(ADP-ribosyl)ation of FoxO3 mediated by PARP1 participates in isoproterenol-induced cardiac hypertrophy
复制标题
PARP1 介导的 FoxO3 聚（ADP-核糖基）化参与异丙肾上腺素诱导的心脏肥大。
DOI：
10.1016/j.bbamcr.2016.09.019
复制
发表时间：
2016-12-01
影响因子：
5.1
通讯作者：
Liu, Peiqing
中科院分区：
文献类型：
--
作者：
Lu, Jing;Zhang, Renwei;Liu, Peiqing
Forkhead box-containing protein， o亚家族3 （FoxO3）转录因子负向调控心肌肥厚，其转录活性受到多种翻译后修饰的精细调节，如磷酸化、乙酰化、泛素化、甲基化和糖基化。在这里，我们介绍了心肌细胞中FoxO3蛋白的一种新的修饰：由聚（adp -核糖）聚合酶-1 （PARP1）介导的聚（adp -核糖）核糖化（PARylation）。这一过程催化了依赖于NAD（+）的adp核糖（PAR）聚合物的合成，并随后通过parp附着在靶蛋白上。用异丙肾上腺素（ISO）孵育原代培养的新生大鼠心肌细胞以诱导肥大，或用含有PARP1 cDNA的重组腺病毒载体（Ad-PARP1）感染。Sprague-Dawley （SD）大鼠采用ISO诱导心肌肥厚，或左室前、后壁注射Ad-PARP1。测定心肌细胞表面积、肥厚生物标志物mRNA表达、超声心动图、心肌形态测定。通过细胞PAR水平检测PARP1活性。采用免疫共沉淀和免疫荧光技术研究PARP1和FoxO3的相互作用。PARP1介导的FoxO3的PARylation促进了其T32、S252和S314位点的磷酸化，触发其核输出，抑制其转录活性和靶基因表达，最终诱导心肌肥厚。此外，3-氨基苯甲酰胺（3AB）和veliparib （ABT-888）对PARP1的沉默或特异性抑制可减轻ISO对FoxO3活性的抑制，从而抑制ISO诱导的心肌肥厚。我们的数据提供了PARP1通过磷酸化FoxO3加剧心脏肥厚的第一个证据。(C) 2016 Elsevier B.V.版权所有
The Forkhead box-containing protein, o subfamily 3 (FoxO3) transcription factor negatively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, methylation and glycosylation. Here, we introduce a novel modification of the FoxO3 protein in cardiomyocytes: poly(ADP-ribosyl)ation (PARylation) mediated by poly(ADP-ribose) polymerase-1 (PARP1). This process catalyzes the NAD(+)-dependent synthesis of polymers of ADP-ribose (PAR) and their subsequent attachment to target proteins by PARPs. Primary-cultured neonatal rat cardiomyocytes were incubated with isoproterenol (ISO) to induce hypertrophy, or were infected with recombinant adenovirus vectors harboring PARP1 cDNA (Ad-PARP1).Sprague-Dawley (SD) rats were treated with ISO to induce cardiac hypertrophy, or were injected with Ad-PARP1 into the anterior and posterior left ventricular walls. Cardiomyocyte surface area, the mRNA expression of hypertrophic biomarkers, echocardiography, morphometry of the hearts were measured. The PARP1 activity was tested by cellular PAR levels. Interactions of PARP1 and FoxO3 were investigated by co-immunoprecipitation and immunofluorescence technique. PARylation of FoxO3 mediated by PARP1 facilitated its phosphorylation at the T32, S252 and S314 sites, triggered its nucleus export and suppressed its transcriptional activity and target genes expression, ultimately inducing cardiac hypertrophy. Additionally, PARP1 silencing or specific inhibition by 3-Aminobenzamide (3AB) and veliparib (ABT-888) alleviated the inhibition of FoxO3 activity by ISO, thus suppressing ISO-induced cardiac hypertrophy. Our data provide the first evidence that PARP1 exacerbates cardiac hypertrophy by PARylation of FoxO3. (C) 2016 Elsevier B.V. All rights reserved.