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PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy

Abstract

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.

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Acknowledgements

This research was supported by grants from the 111 Project (No. B16047 to Pei-qing LIU), National Natural Science Foundation of China (81473205, 81673433 to Pei-qing LIU), Major Project of Platform Construction Education Department of Guangdong Province (No. 2014GKPT002 to Pei-qing LIU), and Special Program for Applied Science and Technology of Guangdong Province (No. 2015B020232009, 2014B020210003 and 2013B090700010 to Pei-qing LIU), National Engineering and Technology Research Center for New Drug Druggability Evaluation (Seed Program of Guangdong Province), Guangzhou Science and Technology Program Project (No. 201604020121 to Pei-qing LIU), Medical Scientific Research Foundation of Guangdong Province (No. A2018078 to Jing LU).

Author contribution

Zhuo-ming LI and Pei-qing LIU designed the study. Qian LI, Shu-ya SUN, Lu-ping WANG, and Zhen GUO performed the experiments. Qian LI, Pan-xia WANG, and Han-wei YANG analyzed the data. Qian LI, Jing LU, and Jian-tao YE wrote the manuscript.

Author information

Competing interests

The authors declare no competing interest.

Correspondence to Jing LU or Pei-qing LIU.

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Keywords

  • heart
  • HMGB1
  • PARP1
  • cardiac hypertrophy
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