From the Department of Cardiology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Theranostics. 2024 Aug 26;14(13):5303-5315. doi: 10.7150/thno.97675. eCollection 2024.
Parkin (an E3 ubiquitin protein ligase) is an important regulator of mitophagy. However, the role of Parkin in viral myocarditis (VMC) remains unclear. Coxsackievirus B3 (CVB3) infection was induced in mice to create VMC. Cardiac function and inflammatory response were evaluated by echocardiography, histological assessment, and molecular analyses. AAV9 (adeno-associated virus 9), transmission electron microscopy (TEM) and western blotting were used to investigate the mechanisms by which Parkin regulates mitophagy and cardiac inflammation. Our data indicated that Parkin- and BNIP3 (BCL2 interacting protein 3 like)-mediated mitophagy was activated in VMC mice and neonatal rat cardiac myocytes (NRCMs) infected with CVB3, which blocked autophagic flux by inhibiting autophagosome-lysosome fusion. Parkin silencing aggravated mortality and accelerated the development of cardiac dysfunction in CVB3-treated mice. While silencing of Parkin did not significantly increase inflammatory response through activating NF-κB pathway and production of inflammatory cytokines post-VMC, the mitophagy activity were reduced, which stimulated the accumulation of damaged mitochondria. Moreover, Parkin silencing exacerbated VMC-induced apoptosis. We consistently found that Parkin knockdown disrupted mitophagy activity and inflammatory response in NRCMs. This study elucidated the important role of Parkin in maintaining cardiac function and inflammatory response by regulating mitophagy activity and the NF-κB pathway during acute VMC. Although the functional impact of mitophagy remains unclear, our findings suggest that Parkin silencing may accelerate VMC development.
Parkin（一种 E3 泛素蛋白连接酶）是线粒体自噬的重要调节因子。然而，Parkin 在病毒性心肌炎（VMC）中的作用尚不清楚。本研究通过在小鼠中诱导柯萨奇病毒 B3（CVB3）感染来建立 VMC 模型。通过超声心动图、组织学评估和分子分析来评估心脏功能和炎症反应。利用 AAV9（腺相关病毒 9）、透射电子显微镜（TEM）和 Western blot 来研究 Parkin 调节线粒体自噬和心脏炎症的机制。研究结果表明，Parkin 和 BNIP3（BCL2 相互作用蛋白 3 样）介导的线粒体自噬在 VMC 小鼠和感染 CVB3 的新生大鼠心肌细胞（NRCMs）中被激活，通过抑制自噬体-溶酶体融合来阻断自噬流。Parkin 沉默加重了 CVB3 处理小鼠的死亡率并加速了心脏功能障碍的发展。虽然 Parkin 沉默通过激活 NF-κB 通路和产生炎症细胞因子来加重 VMC 后的炎症反应，但线粒体自噬活性降低，刺激了受损线粒体的积累。此外，Parkin 沉默加剧了 VMC 诱导的细胞凋亡。研究一致发现，Parkin 敲低破坏了 NRCMs 中线粒体自噬活性和炎症反应。本研究阐明了 Parkin 通过调节线粒体自噬活性和 NF-κB 通路在急性 VMC 中维持心脏功能和炎症反应的重要作用。尽管线粒体自噬的功能影响尚不清楚，但我们的研究结果表明，Parkin 沉默可能加速 VMC 的发展。
