MLKL and CaMKII Are Involved in RIPK3-Mediated Smooth Muscle Cell Necroptosis.
Cells
; 10(9)2021 09 12.
Article
em En
| MEDLINE
| ID: mdl-34572045
ABSTRACT
Receptor interacting protein kinase 3 (RIPK3)-mediated smooth muscle cell (SMC) necroptosis has been shown to contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). However, the signaling steps downstream from RIPK3 during SMC necroptosis remain unknown. In this study, the roles of mixed lineage kinase domain-like pseudokinase (MLKL) and calcium/calmodulin-dependent protein kinase II (CaMKII) in SMC necroptosis were investigated. We found that both MLKL and CaMKII were phosphorylated in SMCs in a murine CaCl2-driven model of AAA and that Ripk3 deficiency reduced the phosphorylation of MLKL and CaMKII. In vitro, mouse aortic SMCs were treated with tumor necrosis factor α (TNFα) plus Z-VAD-FMK (zVAD) to induce necroptosis. Our data showed that both MLKL and CaMKII were phosphorylated after TNFα plus zVAD treatment in a time-dependent manner. SiRNA silencing of Mlkl-diminished cell death and administration of the CaMKII inhibitor myristoylated autocamtide-2-related inhibitory peptide (Myr-AIP) or siRNAs against Camk2d partially inhibited necroptosis. Moreover, knocking down Mlkl decreased CaMKII phosphorylation, but silencing Camk2d did not affect phosphorylation, oligomerization, or trafficking of MLKL. Together, our results indicate that both MLKL and CaMKII are involved in RIPK3-mediated SMC necroptosis, and that MLKL is likely upstream of CaMKII in this process.
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MEDLINE
Assunto principal:
Proteínas Quinases
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Aneurisma da Aorta Abdominal
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Miócitos de Músculo Liso
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Proteína Serina-Treonina Quinases de Interação com Receptores
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
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Necrose
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article