Simvastatin induces autophagic flux to restore cerulein-impaired phagosome-lysosome fusion in acute pancreatitis.
Simvastatin induces autophagic flux to restore cerulein-impaired phagosome-lysosome fusion in acute pancreatitis.
- 2019
BACKGROUND: 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. CONCLUSION: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis. Copyright (c) 2019 Elsevier B.V. All rights reserved. METHODS: 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 (20mg/kg) for 24h followed by 7 hourly cerulein injections and sacrificed 1h after last injection to harvest blood and tissue for analysis. RESULTS: 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.
English
0925-4439
10.1016/j.bbadis.2019.08.006 [doi] S0925-4439(19)30247-9 [pii]
*Anticholesteremic Agents/tu [Therapeutic Use]
*Autophagy/de [Drug Effects]
*Lysosomes/de [Drug Effects]
*Pancreatitis/dt [Drug Therapy]
*Phagosomes/de [Drug Effects]
*Simvastatin/tu [Therapeutic Use]
Acute Disease
Animals
Anticholesteremic Agents/pd [Pharmacology]
Ceruletide/me [Metabolism]
Lysosomes/me [Metabolism]
Lysosomes/pa [Pathology]
Male
Membrane Fusion/de [Drug Effects]
Mice, Inbred C57BL
Pancreatitis/me [Metabolism]
Pancreatitis/pa [Pathology]
Phagosomes/me [Metabolism]
Phagosomes/pa [Pathology]
Simvastatin/pd [Pharmacology]
MedStar Washington Hospital Center
Surgery/General Surgery
Journal Article
BACKGROUND: 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. CONCLUSION: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis. Copyright (c) 2019 Elsevier B.V. All rights reserved. METHODS: 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 (20mg/kg) for 24h followed by 7 hourly cerulein injections and sacrificed 1h after last injection to harvest blood and tissue for analysis. RESULTS: 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.
English
0925-4439
10.1016/j.bbadis.2019.08.006 [doi] S0925-4439(19)30247-9 [pii]
*Anticholesteremic Agents/tu [Therapeutic Use]
*Autophagy/de [Drug Effects]
*Lysosomes/de [Drug Effects]
*Pancreatitis/dt [Drug Therapy]
*Phagosomes/de [Drug Effects]
*Simvastatin/tu [Therapeutic Use]
Acute Disease
Animals
Anticholesteremic Agents/pd [Pharmacology]
Ceruletide/me [Metabolism]
Lysosomes/me [Metabolism]
Lysosomes/pa [Pathology]
Male
Membrane Fusion/de [Drug Effects]
Mice, Inbred C57BL
Pancreatitis/me [Metabolism]
Pancreatitis/pa [Pathology]
Phagosomes/me [Metabolism]
Phagosomes/pa [Pathology]
Simvastatin/pd [Pharmacology]
MedStar Washington Hospital Center
Surgery/General Surgery
Journal Article