Hemin-induced platelet activation and ferroptosis is mediated through ROS-driven proteasomal activity and inflammasome activation: Protection by Melatonin
| Autor: | Kempaiah Kemparaju, Kesturu S. Girish, Somanathapura K. NaveenKumar, Mahadevappa Hemshekhar |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Blood Platelets
Male 0301 basic medicine Proteasome Endopeptidase Complex Programmed cell death Cell Survival Inflammasomes Lipid peroxidation Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Ferroptosis Humans Platelet activation Molecular Biology Melatonin chemistry.chemical_classification Reactive oxygen species Pyroptosis Inflammasome Platelet Activation Glutathione Cell biology Oxidative Stress P-Selectin 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 chemistry Proteasome Cytokines Hemin Molecular Medicine Reactive Oxygen Species 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865:2303-2316 |
| ISSN: | 0925-4439 |
| Popis: | Reactive oxygen species (ROS) are capable of inducing cell death or apoptosis. Recently, we demonstrated that lipid-ROS can mediate ferroptosis and activation of human platelets. Ferroptosis is an intracellular iron-mediated cell death, distinct from classical apoptosis and necrosis, which is mediated through the accumulation of ROS, lipid peroxides and depletion of cellular GSH. Lately, we demonstrated that hemoglobin degradation product hemin induces ferroptosis in platelets via ROS and lipid peroxidation. In this study, we demonstrate that hemin-induced ferroptosis in platelets is mediated through ROS-driven proteasome activity and inflammasome activation, which were mitigated by Melatonin (MLT). Although inflammasome activation is linked with pyroptosis, it is still not clear whether ferroptosis is associated with inflammasome activation. Our study for the first time demonstrates an association of platelet activation/ferroptosis with proteasome activity and inflammasome activation. Although, high-throughput screening has recognized ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent ferroptosis inhibitors, having an endogenous antioxidant such as MLT as ferroptosis inhibitor is of high interest. MLT is a well-known chronobiotic hormone that regulates the circadian rhythms in vertebrates. It also exhibits potent antioxidant and ROS quenching capabilities. MLT can regulate fundamental cellular functions by exhibiting cytoprotective, oncostatic, antiaging, anti-venom, and immunomodulatory activities. The ROS scavenging capacity of MLT is key for its cytoprotective and anti-apoptotic properties. Considering the anti-ferroptotic and anti-apoptotic potentials of MLT, it could be a promising clinical application to treat hemolytic, thrombotic and thrombocytopenic conditions. Therefore, we propose MLT as a pharmacological and therapeutic agent to inhibit ferroptosis and platelet activation. |
| Databáze: | OpenAIRE |
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