PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy
PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy
复制标题
PARP1 与 HMGB1 相互作用并促进其在病理性心肌肥厚中的核输出。
DOI：
10.1038/s41401-018-0044-4
复制
发表时间：
2019-05-01
影响因子：
8.2
通讯作者：
Liu, Pei-qing
中科院分区：
文献类型：
--
作者：
Li, Qian;Li, Zhuo-ming;Liu, Pei-qing
高迁移率族蛋白1(HMGB1)根据其亚细胞位置的不同表现出不同的功能，这种功能受到各种翻译后修饰的精细调节，如乙酰化。核型HMGB1可预防心肌肥大，而其外源蛋白可诱导心肌肥大反应。本研究旨在探讨聚腺苷二磷酸核糖聚合酶1(PARP1)和HMGB1在病理性心肌肥厚过程中的调控关系。原代培养的新生大鼠心肌细胞分别与血管紧张素II(Ang II)、苯肾上腺素(PE)和异丙肾上腺素(ISO)3种心肌肥大刺激剂孵育，测定细胞表面积和肥大标志物的mRNA表达。PARP1的催化活性显著增强，同时HMGB1被排除在核外。腺病毒PARP1(Ad-PARP1)过表达可促进HMGB1的核输出，促进HMGB1在细胞外的分泌，加重心肌细胞肥大，HMGB1过表达可减轻这种作用。PE处理也有类似的结果，但这种作用被PARP1沉默或其特异性抑制剂AG14361广泛抑制。此外，在腹主动脉缩窄(AAC)术后7天，给SD大鼠腹腔注射3-氨基苯甲酰胺(3AB，20 mg/kg，一种公认的PARP1抑制剂)，连续6周，测量心脏的超声心动图和形态计量学。3AB可减轻AAC引起的核HMGB1蛋白移位、心肌肥厚和心功能不全。我们的研究提供了一个新的证据，PARP1与HMGB1结合并加速其从细胞核到细胞质的移位，最终导致心肌肥大。
High-mobility group box 1 (HMGB1) exhibits various functions according to its subcellular location, which is finely conditioned by diverse post-translational modifications, such as acetylation. The nuclear HMGB1 may prevent from cardiac hypertrophy, whereas its exogenous protein is proven to induce hypertrophic response. This present study sought to investigate the regulatory relationships between poly(ADP-ribose) polymerase 1 (PARP1) and HMGB1 in the process of pathological myocardial hypertrophy. Primary-cultured neonatal rat cardiomyocytes (NRCMs) were respectively incubated with three cardiac hypertrophic stimulants, including angiotensin II (Ang II), phenylephrine (PE), and isoproterenol (ISO), and cell surface area and the mRNA expression of hypertrophic biomarkers were measured. the catalytic activity of PARP1 was remarkably enhanced, meanwhile HMGB1 excluded from the nucleus. PARP1 overexpression by infecting with adenovirus PARP1 (Ad-PARP1) promoted the nuclear export of HMGB1, facilitated its secretion outside the cell, aggravated cardiomyocyte hypertrophy, which could be alleviated by HMGB1 overexpression. PE treatment led to the similar results, while that effect was widely depressed by PARP1 silencing or its specific inhibitor AG14361. Moreover, SD rats were intraperitoneally injected with 3-aminobenzamide (3AB, 20 mg/kg every day, a well-established PARP1 inhibitor) 7 days after abdominal aortic constriction (AAC) surgery for 6 weeks, echocardiography and morphometry of the hearts were measured. Pre-treatment of 3AB relieved AAC-caused the translocation of nuclear HMGB1 protein, cardiac hypertrophy, and heart dysfunction. Our research offers a novel evidence that PARP1 combines with HMGB1 and accelerates its translocation from nucleus to cytoplasm, and the course finally causes cardiac hypertrophy.