Yang Yiyuan, Zhang Kai, Huang Shifang, Chen Wei, Mao Hui, Ouyang Xueqian, Chen Linxi, Li Lanfang
School of Pharmaceutical Science, Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China.
J Cell Physiol. 2022 Apr;237(4):2230-2248. doi: 10.1002/jcp.30685. Epub 2022 Feb 6.
Cardiac hypertrophy is a leading cause of cardiac morbidity and mortality worldwide. Apelin is the endogenous ligand for the G protein-coupled receptor, APJ. Previously, we have revealed that apelin-13 can induce cardiomyocyte hypertrophy by activating the autophagy pathway. However, the precise mechanism through which apelin-13 regulates reticulophagy to participate in cardiomyocyte hypertrophy remains unclear. Herein, we observed that apelin-13-induced cardiomyocyte hypertrophy by activating FAM134B-dependent reticulophagy via the Pannexin-1/P2X7 signal pathway. Furthermore, we found that apelin-13 stimulated the opening of Pannexin-1 hemichannel and increased extracellular ATP (eATP) levels, which activated the P2X7 purinergic receptor. Activation of the Pannexin-1/eATP/P2X7 axis subsequently led to FAM134B-dependent reticulophagy. Moreover, inhibition of the Pannexin-1/P2X7 axis and FAM134B-dependent reticulophagy reversed apelin-13-induced cardiomyocyte hypertrophy. Based on our present findings, apelin-13/APJ induces cardiomyocyte hypertrophy by activating the Pannexin-1/P2X7 axis and FAM134B-dependent reticulophagy.
心脏肥大是全球范围内心脏发病和死亡的主要原因。Apelin是G蛋白偶联受体APJ的内源性配体。此前，我们已经揭示apelin-13可通过激活自噬途径诱导心肌细胞肥大。然而，apelin-13调节网织自噬参与心肌细胞肥大的确切机制仍不清楚。在此，我们观察到apelin-13通过Pannexin-1/P2X7信号通路激活FAM134B依赖的网织自噬来诱导心肌细胞肥大。此外，我们发现apelin-13刺激Pannexin-1半通道开放并增加细胞外ATP（eATP）水平，从而激活P2X7嘌呤能受体。Pannexin-1/eATP/P2X7轴的激活随后导致FAM134B依赖的网织自噬。此外，抑制Pannexin-1/P2X7轴和FAM134B依赖的网织自噬可逆转apelin-13诱导的心肌细胞肥大。基于我们目前的研究结果，apelin-13/APJ通过激活Pannexin-1/P2X7轴和FAM134B依赖的网织自噬诱导心肌细胞肥大。
