Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165530. doi: 10.1016/j.bbadis.2019.08.006. Epub 2019 Aug 6.
During pancreatitis, autophagy is activated, but lysosomal degradation of dysfunctional organelles including mitochondria is impaired, resulting in acinar cell death. Retrospective cohort analyses demonstrated an association between simvastatin use and decreased acute pancreatitis incidence.
We examined whether simvastatin can protect cell death induced by cerulein and the mechanisms involved during acute pancreatitis. Mice were pretreated with DMSO or simvastatin (20 mg/kg) for 24 h followed by 7 hourly cerulein injections and sacrificed 1 h after last injection to harvest blood and tissue for analysis.
Pancreatic histopathology revealed that simvastatin reduced necrotic cell death, inflammatory cell infiltration and edema. We found that cerulein triggered mitophagy with autophagosome formation in acinar cells. However, autophagosome-lysosome fusion was impaired due to altered levels of LAMP-1, AMPK and ULK-1, resulting in autophagosome accumulation (incomplete autophagy). Simvastatin abrogated these effects by upregulating LAMP-1 and activating AMPK which phosphorylated ULK-1, resulting in increased formation of functional autolysosomes. In contrast, autophagosomes accumulated in control group during pancreatitis. The effects of simvastatin to promote autophagic flux were inhibited by chloroquine. Mitochondria from simvastatin-treated mice were resistant to calcium overload compared to control, suggesting that simvastatin induced mitochondrial quality control to eliminate susceptible mitochondria. Clinical specimens showed a significant increase in cell-free mtDNA in plasma during pancreatitis compared to normal controls. Furthermore, genetic deletion of parkin abrogated the benefits of simvastatin.
Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.
在胰腺炎发生时，自噬被激活，但包括线粒体在内的功能失调细胞器的溶酶体降解受损，导致腺泡细胞死亡。回顾性队列分析表明，辛伐他汀的使用与急性胰腺炎发病率的降低有关。
我们研究了辛伐他汀是否可以保护细胞免受 cerulein 诱导的细胞死亡，并研究了急性胰腺炎发生过程中的相关机制。小鼠用 DMSO 或辛伐他汀（20mg/kg）预处理 24 小时，然后每 7 小时接受 cerulein 注射，最后一次注射后 1 小时处死，采集血液和组织进行分析。
胰腺组织病理学显示，辛伐他汀减少了坏死性细胞死亡、炎症细胞浸润和水肿。我们发现 cerulein 在腺泡细胞中触发了 mitophagy，形成自噬体。然而，由于 LAMP-1、AMPK 和 ULK-1 水平的改变，自噬体-溶酶体融合受损，导致自噬体积累（不完全自噬）。辛伐他汀通过上调 LAMP-1 和激活 AMPK 来拮抗这些作用，AMPK 磷酸化 ULK-1，导致功能性自溶酶体的形成增加。相反，在胰腺炎期间，对照组中的自噬体积累。氯喹抑制了辛伐他汀促进自噬流的作用。与对照组相比，来自辛伐他汀处理的小鼠的线粒体对钙超载具有更强的抗性，表明辛伐他汀诱导了线粒体质量控制以消除易感性线粒体。临床标本显示，与正常对照组相比，胰腺炎患者血浆中的细胞游离 mtDNA 显著增加。此外，parkin 的基因缺失消除了辛伐他汀的益处。
我们的研究结果揭示了辛伐他汀在增强自噬流以防止胰腺细胞损伤和胰腺炎方面的新作用。
