Simvastatin treatment induces morphology alterations and apoptosis in murine cochlear neuronal cells

Park, Do‐Sim; So, Hong-Seob; Lee, Jeong-Han; Park, Hyun-Young; Lee, Young Jin; Cho, Ji-Hyun; Yoon, Kui-Hyun; Park, Channy; Yun, Ki-Jung; Park, Raekil

doi:10.1080/00016480802163358

Cited by 20 publications

(20 citation statements)

References 17 publications

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“…The nerve fiber damage was extensive in rats receiving 80 mg/ kg. The effects of statins on the nervous system are controversial, since some authors suggest neuroprotective effects whilst others have demonstrated that statins induced neuronal apoptosis [23]. A study conducted by Otruba et al, [24] confirmed definite damage to peripheral nerves in patients taking statins for more than 2 years.…”

Section: The Morphometric Resultsmentioning

confidence: 88%

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Mokhmer¹,

Saber²,

Hamouda³

et al. 2017

J Cytol Histol

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Section: The Morphometric Resultsmentioning

confidence: 88%

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Mokhmer¹,

Saber²,

Hamouda³

et al. 2017

J Cytol Histol

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“…Taken together, these results implicated that mevalonate does not play a major role in simvastatin-mediated protection. Simvastatin at higher doses has been shown to alter cellular morphology (41,42). Although the biological significance of simvastatin-induced cellular morphological changes varies depending on cell type, we took this as one measure to evaluate the cellular uptake of mevalonate in airway epithelial cells.…”

Section: Mevalonate Supplement Does Not Abrogate Simvastatin-conferrementioning

confidence: 99%

Statin-Conferred Enhanced Cellular Resistance against Bacterial Pore-Forming Toxins in Airway Epithelial Cells

Statt

Ruan

Hung

et al. 2015

Am J Respir Cell Mol Biol

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Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10-1,000 nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, a-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin associated bacterial infections.Keywords: airway epithelium; pneumolysin; simvastatin; cholesterol; pneumonia Clinical RelevanceOur study dissects the cellular and molecular protection mechanisms of statins in an isolated airway epithelial cell-bacterial pore-forming toxin context. This research can fill large gaps in our understanding of how statins contribute to the reduced pathology observed during pneumonia and other bacterial infections. The better understanding of the molecular mechanisms in the statin-mediated protection will further affect the therapeutic development of host-centric approach therapies in combating microbial infections.

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“…Accordingly, simvastatin does not only trigger apoptosis, the suicidal death of nucleated cells [31-39], but by the same token triggers eryptosis, the suicidal erythrocyte death. The simvastatin concentrations required for the stimulation of eryptosis were in the range of concentrations (0.9 µg/ml) measured in the plasma of patients [39].…”

Section: Discussionmentioning

confidence: 99%

“…Simvastatin has been shown to stimulate apoptosis of neurons [31] and tumor cells [32-39]. In view of its effect in tumor cells simvastatin was considered as a potential therapeutic option in malignancy [32, 35-37].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin, a Novel Stimulator of Eryptosis, the Suicidal Erythrocyte Death

Bhuyan

Nüßle

Cao

et al. 2017

Cell Physiol Biochem

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Background/Aims: The 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase inhibitor simvastatin has been shown to trigger apoptosis of several cell types. The substance has thus been proposed as an additional treatment of malignancy. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death. Hallmarks of eryptosis include cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the extracellular face of the erythrocyte cell membrane. Signaling contributing to stimulation of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), induction of oxidative stress, increase of ceramide abundance, and activation of SB203580-sensitive p38 kinase. The present study explored, whether simvastatin induces eryptosis and aimed to shed light on cellular mechanisms involved. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. Results: A 48 h exposure of human erythrocytes to simvastatin (1 µg/ml) significantly decreased the forward scatter, significantly augmented the percentage of annexin-V-binding cells, significantly increased Fluo3-fluorescence, and significantly enhanced DCFDA fluorescence. Simvastatin tended to increase ceramide abundance, an effect, however, escaping statistical significance. The effect of simvastatin on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺ and by addition of SB203580 (2 µM). Conclusions: Simvastatin stimulates eryptosis, an effect at least in part due to Ca²⁺ entry, oxidative stress, and p38 kinase.

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Simvastatin treatment induces morphology alterations and apoptosis in murine cochlear neuronal cells

Cited by 20 publications

References 17 publications

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Statin-Conferred Enhanced Cellular Resistance against Bacterial Pore-Forming Toxins in Airway Epithelial Cells

Simvastatin, a Novel Stimulator of Eryptosis, the Suicidal Erythrocyte Death

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