School of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, 825, Zhangheng Road, Pudong New District, Shanghai, 201203, People's Republic of China.
State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, People's Republic of China.
Cell Mol Life Sci. 2023 May 23;80(6):161. doi: 10.1007/s00018-023-04805-9.
Pressure overload-induced pathological cardiac hypertrophy is an independent predecessor of heart failure (HF), which remains the leading cause of worldwide mortality. However, current evidence on the molecular determinants of pathological cardiac hypertrophy is still inadequacy. This study aims to elucidate the role and mechanisms of Poly (ADP-ribose) polymerases 16 (PARP16) in the pathogenesis of pathological cardiac hypertrophy.
Gain and loss of function approaches were used to demonstrate the effects of genetic overexpression or deletion of PARP16 on cardiomyocyte hypertrophic growth in vitro. Ablation of PARP16 by transducing the myocardium with serotype 9 adeno-associated virus (AAV9)-encoding PARP16 shRNA were then subjected to transverse aortic construction (TAC) to investigate the effect of PARP16 on pathological cardiac hypertrophy in vivo. Co-immunoprecipitation (IP) and western blot assay were used to detect the mechanisms of PARP16 in regulating cardiac hypertrophic development.
PARP16 deficiency rescued cardiac dysfunction and ameliorated TAC-induced cardiac hypertrophy and fibrosis in vivo, as well as phenylephrine (PE)-induced cardiomyocyte hypertrophic responses in vitro. Whereas overexpression of PARP16 exacerbated hypertrophic responses including the augmented cardiomyocyte surface area and upregulation of the fetal gene expressions. Mechanistically, PARP16 interacted with IRE1α and ADP-ribosylated IRE1α and then mediated the hypertrophic responses through activating the IRE1α-sXBP1-GATA4 pathway.
Collectively, our results implicated that PARP16 is a contributor to pathological cardiac hypertrophy at least in part via activating the IRE1α-sXBP1-GATA4 pathway, and may be regarded as a new potential target for exploring effective therapeutic interventions of pathological cardiac hypertrophy and heart failure.
压力超负荷诱导的病理性心肌肥厚是心力衰竭（HF）的独立前驱，它仍然是全球死亡的主要原因。然而，目前关于病理性心肌肥厚的分子决定因素的证据仍然不足。本研究旨在阐明多聚（ADP-核糖）聚合酶 16（PARP16）在病理性心肌肥厚发病机制中的作用和机制。
采用基因过表达或缺失的方法，观察 PARP16 在体外心肌细胞肥大生长中的作用。用血清型 9 腺相关病毒（AAV9）编码的 PARP16 shRNA 转导心肌细胞，以消除 PARP16，然后进行横主动脉缩窄（TAC），以研究 PARP16 在病理性心肌肥厚中的作用。用免疫共沉淀（IP）和Western blot 检测 PARP16 调节心脏肥大发育的机制。
PARP16 缺乏可挽救心脏功能障碍，并改善体内 TAC 诱导的心肌肥厚和纤维化，以及苯肾上腺素（PE）诱导的心肌细胞肥大反应。而过表达 PARP16 则加剧了肥大反应，包括心肌细胞表面积增大和胎儿基因表达上调。机制上，PARP16 与 IRE1α 相互作用，并对其进行 ADP-核糖基化，然后通过激活 IRE1α-sXBP1-GATA4 途径介导肥大反应。
总之，我们的研究结果表明，PARP16 通过激活 IRE1α-sXBP1-GATA4 途径至少部分参与病理性心肌肥厚的发生，可能被视为探索病理性心肌肥厚和心力衰竭有效治疗干预的新的潜在靶点。
