Honit Piplani1, Stefanie Marek-Iannucci1, Jon Sin1, Jean Hou2, Toshimasa Takahashi3, Ankush Sharma4, Juliana de Freitas Germano1, Richard T Waldron5, Hannaneh Saadaeijahromi1, Yang Song1, Aiste Gulla6, Bechien Wu7, Aurelia Lugea5, Allen M Andres1, Herbert Y Gaisano3, Roberta A Gottlieb8, Stephen J Pandol9. 1. Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 2. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 3. Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada. 4. Institute of Biosciences and Department of Informatics, University of Oslo, Norway. 5. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 6. Department of Surgery, MedStar Georgetown University Hospital, USA; Vilnius University Hospital Santaros Klinikos, Lithuania. 7. Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA. 8. Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: roberta.gottlieb@cshs.org. 9. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: stephen.pandol@cshs.org.
Abstract
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. 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 (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. 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. CONCLUSION: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.
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. 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 (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. 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. CONCLUSION: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.
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