RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage

Zhou, Huiling; Liu, Lijun; Ma, Xiaolong; Wang, Jian; Yang, Jinfu; Zhou, Xin; Yang, Yifeng; Liu, Haidan

doi:10.1007/s11010-020-03985-3

Cited by 27 publications

(17 citation statements)

References 46 publications

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“…In contrast, a study conducted by Zhou et al showed that in vinblastine-induced rat myocardial injury, both MLKL level and phosphorylation of CaMKII were increased. Furthermore, the MLKL inhibitor necrosulfonamide (NSA) partially inhibited cell death [ 10 ]. Yang et al also found that both MLKL and CaMKII were phosphorylated in tissue samples gathered from mice exposed to a combined model of myocardial ischemia-reperfusion injury and chronic pain [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, Zhang et al reported that during ischemia-reperfusion or doxorubicin-induced myocardial necroptosis, RIPK3 may signal through calcium/calmodulin-dependent protein kinase II (CaMKII) instead of MLKL [ 9 ]. Activation of CaMKII was also detected in vinblastine or tunicamycin-induced myocardial necroptosis, and in Bisphenol A-induced coronary endothelial cell necroptosis [ 10 , 11 , 12 ]. The precise roles of MLKL and CaMKII in SMC necroptosis remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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MLKL and CaMKII Are Involved in RIPK3-Mediated Smooth Muscle Cell Necroptosis

Zhou

DeRoo

Yang

et al. 2021

Cells

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MLKL and CaMKII Are Involved in RIPK3-Mediated Smooth Muscle Cell Necroptosis

Zhou

DeRoo

Yang

et al. 2021

Cells

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“…Necroptosis is involved in host defensive responses, chronic inflammation, and tissue damage, such as inflammation, hemolysis, and atherosclerosis ( Frank and Vince, 2019 ). The formation of receptor interacting protein kinase-1 and -3/mixed lineage kinase domain-like protein (RIP1/RIP3/MLKL)-containing complexes in necrotic bodies can initiate the necroptosis pathway ( Zhou et al, 2021 ). RPI1/RIP3/MLKL is expressed in ERMCs, and its content is higher than that in mitochondria.…”

Section: The Function Of Endoplasmic Reticulum-mitochondria Contactsmentioning

confidence: 99%

Endoplasmic Reticulum-Mitochondria Contacts: A Potential Therapy Target for Cardiovascular Remodeling-Associated Diseases

Wang

Zhang

Wen

et al. 2021

Front. Cell Dev. Biol.

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Cardiovascular remodeling occurs in cardiomyocytes, collagen meshes, and vascular beds in the progress of cardiac insufficiency caused by a variety of cardiac diseases such as chronic ischemic heart disease, chronic overload heart disease, myocarditis, and myocardial infarction. The morphological changes that occur as a result of remodeling are the critical pathological basis for the occurrence and development of serious diseases and also determine morbidity and mortality. Therefore, the inhibition of remodeling is an important approach to prevent and treat heart failure and other related diseases. The endoplasmic reticulum (ER) and mitochondria are tightly linked by ER-mitochondria contacts (ERMCs). ERMCs play a vital role in different signaling pathways and provide a satisfactory structural platform for the ER and mitochondria to interact and maintain the normal function of cells, mainly by involving various cellular life processes such as lipid metabolism, calcium homeostasis, mitochondrial function, ER stress, and autophagy. Studies have shown that abnormal ERMCs may promote the occurrence and development of remodeling and participate in the formation of a variety of cardiovascular remodeling-associated diseases. This review focuses on the structure and function of the ERMCs, and the potential mechanism of ERMCs involved in cardiovascular remodeling, indicating that ERMCs may be a potential target for new therapeutic strategies against cardiovascular remodeling-induced diseases.

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“…Mixed lineage kinase domain-like protein (MLKL) is the substrate of RIP3, and numerous studies have demonstrated that the formation of a complex between RIP3 and MLKL is an essential step for inducing programmed necrosis [ 15 , 16 ]. RIP3 and MLKL are significantly increased in vinblastine-caused myocardial damage [ 17 ]. Besides, inhibition of RIP3 and MLKL activation attenuates heart failure [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

RIP3 Contributes to Cardiac Hypertrophy by Influencing MLKL-Mediated Calcium Influx

Xue

Shi

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Receptor-interacting protein 3(RIP3), a RIP family member, has been reported as a critical regulator of necroptosis and involves in the pathogenesis of various heart diseases. However, its role in the development of myocardial hypertrophy after pressure overload is unclear. We aimed to investigate the roles of RIP3 in pathological cardiac hypertrophy. A rat model of myocardial hypertrophy induced by the aortic banding method was used in this study. Neonatal rat cardiomyocytes (NRCMs) were stimulated with angiotensin II (Ang-II) or phenylephrine (PE) to induce neurohumoral stress. Our results showed that RIP3 level was significantly elevated in the hypertrophic myocardium tissues from patients, rats subjected to AB surgery, and NRCMs treated with Ang-II or PE. After downregulation of RIP3 expression in NRCMs, the phenotypes of myocardial hypertrophy were obviously alleviated. In mechanism, we demonstrated that RIP3 interacts with mixed lineage kinase domain-like protein (MLKL) and promotes its cell membrane localization to increase the influx of calcium within cells, thereby mediating the development of myocardial hypertrophy. More interestingly, we found the blockage of calcium influx by 2-aminoethoxydiphenyl borate, and lanthanum chloride efficiently reverses RIP3-induced cardiac remodeling in NRCMs. Taken together, our findings indicate a key role of the RIP3-MLKL signaling pathway in myocardial hypertrophy, which may be a novel promising treatment strategy for myocardial hypertrophy.

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RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage

Cited by 27 publications

References 46 publications

MLKL and CaMKII Are Involved in RIPK3-Mediated Smooth Muscle Cell Necroptosis

MLKL and CaMKII Are Involved in RIPK3-Mediated Smooth Muscle Cell Necroptosis

Endoplasmic Reticulum-Mitochondria Contacts: A Potential Therapy Target for Cardiovascular Remodeling-Associated Diseases

RIP3 Contributes to Cardiac Hypertrophy by Influencing MLKL-Mediated Calcium Influx

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