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

Xue, Honghong; Shi, Hongtao; Zhang, Fan; Li, Hao; Li, Chao; Han, Qinghua

doi:10.1155/2022/5490553

Cited by 7 publications

(3 citation statements)

References 44 publications

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“…After the downregulation of RIP3 expression in NRCMs, the phenotypes of myocardial hypertrophy were obviously alleviated. Research has shown that RIP3 interacts with mixed lineage kinase domainlike protein (MLKL) and promotes its cell membrane localization to increase the influx of calcium within cells, thereby mediating the development of myocardial hypertrophy [47]. Our experimental results showed a key role of the RIP3-MLKL signaling pathway in myocardial hypertrophy.…”

Section: Discussionmentioning

confidence: 56%

The Regulatory Effect of Receptor-Interacting Protein Kinase 3 on CaMKIIδ in TAC-Induced Myocardial Hypertrophy

Qian,

Zhang,

Cao

et al. 2023

IJMS

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Necroptosis is a newly discovered mechanism of cell death, and its key regulatory role is attributed to the interaction of receptor-interacting protein kinases (RIPKs) RIPK1 and RIPK3. Ca2+/calmodulin-dependent protein kinase (CaMKII) is a newly discovered RIPK3 substrate, and its alternative splicing plays a fundamental role in cardiovascular diseases. In the present study, we aimed to explore the role and mechanism of necroptosis and alternative splicing of CaMKIIδ in myocardial hypertrophy. Transverse aortic constriction (TAC) was performed on wild-type and knockout mice to establish the model of myocardial hypertrophy. After 3 weeks, echocardiography, cardiac index, cross-sectional area of myocardial cells, hypertrophic gene expression, myocardial damage, and fibers were assessed. Moreover, we detected the levels of inflammatory factors (IL-6 and TNF-α) and examined the expressions of necroptosis-related proteins RIPK3, RIPK1, and phosphorylated MLKL. Meanwhile, we tested the expression levels of splicing factors ASF/SF2 and SC-35 in an attempt to explore CaMKII δ. The relationship between variable splicing disorder and the expression levels of splicing factors ASF/SF2 and SC-35. Further, we also investigated CaMKII activation, oxidative stress, and mitochondrial ultrastructure. In addition, wild-type mice were administered with a recombinant adeno-associated virus (AAV) carrying RIPK3, followed by TAC surgery to construct a model of myocardial hypertrophy, and the above-mentioned indicators were tested after 3 weeks. The results showed that RIPK3 deficiency could alleviate cardiac dysfunction, myocardial injury, aggravation of necrosis, and CaMKII activation induced by TAC surgery in mice with myocardial hypertrophy. Tail vein injection of AAV could reverse cardiac dysfunction, myocardial damage, aggravation of necrosis, and CaMKII activation in mice with myocardial hypertrophy. These results proved that RIPK3 could be used as a molecular intervention target for the prevention and treatment of myocardial hypertrophy.

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Section: Discussionmentioning

confidence: 56%

The Regulatory Effect of Receptor-Interacting Protein Kinase 3 on CaMKIIδ in TAC-Induced Myocardial Hypertrophy

Qian,

Zhang,

Cao

et al. 2023

IJMS

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“…Upon activation, RIP3 recruits and phosphorylates the lineage kinase domain-like protein (MLKL), leading to its oligomerization and localization to the plasma membrane. Ultimately, this results in cell membrane rupture and cell death [ 15 , 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

HIST3H2A promotes the progression of prostate cancer through inhibiting cell necroptosis

Yang,

Ruan,

2024

BMC Cancer

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In recent years, there has been an increase in the incidence and mortality rates of prostate cancer (PCa). However, the specific molecular mechanisms underlying its occurrence and development remain unclear, necessitating the identification of new therapeutic targets. Through bioinformatics analysis, we discovered a previously unstudied differential gene called HIST3H2A in prostate cancer. Our study revealed that HIST3H2A is highly expressed in PCa tissues, as confirmed by analysis of both the GEO and UALCAN databases. Further analysis using the KEGG database demonstrated that HIST3H2A regulates the pathway of programmed necroptosis in cells. Additionally, we observed significant up-regulation of HIST3H2A in PCa tissues and cell lines. HIST3H2A was found to regulate cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process in tumors. Notably, HIST3H2A’s role in regulating programmed necroptosis in prostate cancer cells differs from its role in apoptosis. In vitro and in vivo experiments collectively support the key role of HIST3H2A in promoting the development of prostate cancer, highlighting its potential as a therapeutic target for patients with PCa.

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“…As a result of intramolecular auto and trans-phosphorylation of RIP1/RIP3, mixed lineage kinase domain-like protein (MLKL) is recruited, leading to membrane pore formation, subsequent disruption of membrane integrity, and ultimately necrosis. Currently, there is growing interest in research to dissect various mechanisms governing necroptosis, with recent studies highlighting the role of necroptosis, particularly RIPK3 pathway-mediated necroptosis, as a promising future treatment strategy for HCM (12)(13)(14)(15). Zou et al have presented that a novel necroptotic loop compromised by CB2R serves as a critical driving force of diabetic heart dysfunction by recruiting the coregulator BACH2 (previously unrecognized as a cardiomyocyte transcription factor) to transcriptionally repress the expression of necroptosis (16).…”

Section: Introductionmentioning

confidence: 99%

Necroptosis and immune infiltration in hypertrophic cardiomyopathy: novel insights from bioinformatics analyses

Hou,

Fei,

Jia

2024

Front. Cardiovasc. Med.

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BackgroundHypertrophic Cardiomyopathy (HCM), a widespread genetic heart disorder, is largely associated with sudden cardiac fatality. Necroptosis, an emerging type of programmed cell death, plays a fundamental role in several cardiovascular diseases.AimThis research utilized bioinformatics analysis to investigate necroptosis's implication in HCM.MethodsThe study retrieved RNA sequencing datasets GSE130036 and GSE141910 from the Gene Expression Omnibus (GEO) database. It detected necroptosis-linked differentially expressed genes (NRDEGs) by reviewing both the gene set for necroptosis and the differently expressed genes (DEGs). The enriched signaling pathway of HCM was assessed using GSEA, while common DEGs were studied through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Concurrently, the Protein-Protein Interaction network (PPI) proved useful for identifying central genes. CIBERSORT facilitated evaluating the correlation between distinct immune cell-type prevalence and NRDEGs by analyzing immune infiltration patterns. Lastly, GSE141910 dataset validated the expression ranks of NRDEGs and immune-cell penetration.ResultsThe investigation disclosed significant enrichment and activation of the necroptosis pathway in HCM specimens. Seventeen diverse genes, including CYBB, BCL2, and JAK2 among others, were identified in the process. PPI network scrutiny classified nine of these genes as central genes. Results from GO and KEGG enrichment analyses showed substantial connections of these genes to pathways pertaining to the HIF-1 signaling track, necroptosis, and NOD-like receptor signaling process. Moreover, an imbalance in M2 macrophage cells in HCM samples was observed. Finally, CYBB, BCL2, and JAK2 emerged as vital genes and were validated using the GSE141910 dataset.ConclusionThese results indicate necroptosis as a probable underlying factor in HCM, with immune cell infiltration playing a part. Additionally, CYBB, BCL2, JAK2 could act as potential biomarkers for recognizing HCM. This information forms crucial insights into the basic mechanisms of HCM and could enhance its diagnosis and management.

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

Cited by 7 publications

References 44 publications

The Regulatory Effect of Receptor-Interacting Protein Kinase 3 on CaMKIIδ in TAC-Induced Myocardial Hypertrophy

The Regulatory Effect of Receptor-Interacting Protein Kinase 3 on CaMKIIδ in TAC-Induced Myocardial Hypertrophy

HIST3H2A promotes the progression of prostate cancer through inhibiting cell necroptosis

Necroptosis and immune infiltration in hypertrophic cardiomyopathy: novel insights from bioinformatics analyses

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