Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
Bank of China Ltd., Guangzhou 510610, PR China.
Mol Cell Endocrinol. 2018 Oct 15;474:137-150. doi: 10.1016/j.mce.2018.02.020. Epub 2018 Mar 1.
The activation of signal transducer and activator of transcription 3 (STAT3) positively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse extracellular growth factors and cytokines. Here, we introduce novel evidence that poly(ADP-ribose) polymerase 1 (PARP1) interacts with STAT3 and promotes its activation in cardiomyocytes and rat heart tissues. PARP1 activity and phosphorylated STAT3 were augmented by hypertrophic stimuli both in vitro and in vivo. Infection of PARP1 adenovirus induced cardiomyocyte hypertrophy, which could be prevented by STAT3 knockdown or inhibition. Additionally, PARP1 enhanced STAT3 phosphorylation level, nuclear accumulation and transcriptional activity. Mechanistically, PARP1 interacts with STAT3 and retains active phosphorylated-STAT3 in nucleus. In conclusion, our findings provide the first evidence that PARP1 exacerbates cardiac hypertrophy by stabilizing active phosphorylated-STAT3, which suggests that multi-target therapeutic strategies counteracting PARP1 activity and STAT3 activation would be potential for treating cardiovascular diseases.
信号转导子和转录激活子 3（STAT3）的激活正向调节心肌肥大，其转录活性受到多种细胞外生长因子和细胞因子的精细调节。在这里，我们介绍了新的证据，表明多聚（ADP-核糖）聚合酶 1（PARP1）与 STAT3 相互作用，并促进其在心肌细胞和大鼠心脏组织中的激活。PARP1 活性和磷酸化 STAT3 在体外和体内均由肥大刺激物增强。PARP1 腺病毒感染诱导心肌细胞肥大，这可以通过 STAT3 敲低或抑制来预防。此外，PARP1 增强了 STAT3 的磷酸化水平、核积累和转录活性。从机制上讲，PARP1 与 STAT3 相互作用，并将活性磷酸化-STAT3 保留在核内。总之，我们的研究结果首次提供了证据表明，PARP1 通过稳定活性磷酸化-STAT3 加剧心脏肥大，这表明针对 PARP1 活性和 STAT3 激活的多靶点治疗策略可能是治疗心血管疾病的潜在方法。
