title: The Different Effects of Atorvastatin and Pravastatin on Cell Death and PARP Activity in Pancreatic NIT-1 Cells.
abstract: Statins have been widely used drugs for lowering low-density lipoprotein and for preventing heart attack and stroke. However, the increased risk for developing diabetes during extended stain use and the molecular mechanisms remain unclear. The objective of this study was to elucidate the signaling pathway and biological function between necrosis and autophagy induced by atorvastatin (AS) and pravastatin (PS). Here we observed that atorvastatin (AS) can increase intracellular reactive oxygen species (ROS) and induce necrotic cell death and autophagy in NIT-1 cells, whereas pravastatin (PS) does not cause ROS and cell death but also induces autophagy. PARP1 exhibited a dual role in modulating necrosis and autophagy in AS- and PS-treated NIT-1 cells through RIP1-RIP3-MLKL pathway and PARP1-AMPK-mTOR pathway. Lastly, AS treatment induced mitochondrial morphology injury significantly more than PS treatment did. Thus, the PARP1 activation should be considered in the development of effective statin therapies for diabetes. Future studies may examine specific mechanisms and pathways in mitochondria, autophagy, and oxidative stressin vivo.
authors.affiliation: Diabetes Research Laboratory, Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan; Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Diabetes Research Laboratory, Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan; Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Integrative Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chin-San
authors.initials: CS
authors.lastname: Liu
authors.affiliation: Diabetes Research Laboratory, Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Integrative Medicine, China Medical University, Taichung, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Ming-Chia
authors.identifier: 0000-0002-3912-9157
authors.initials: MC
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D000069059:Atorvastatin; D000071137:Poly (ADP-Ribose) Polymerase-1; D017035:Pravastatin