ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis

Horiguchi, Haruki; Kadomatsu, Tsuyoshi; Yamashita, Tomoya; Yumoto, Shinsei; Terada, Kazutoyo; Sato, Michio; Morinaga, Jun; Miyata, Keishi; Oike, Yuichi

doi:10.1038/s42003-023-05338-4

Cited by 3 publications

(5 citation statements)

References 53 publications

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“…The abnormal expression of CCL18 [206], EOMES (eomesodermin) [207], GZMA (granzyme A) [ [262], IL24 [263], IL9 [264], CHI3L1 [265], CDH1 [266], OLIG2 [267], NKX6-2 [268]. HK2 [269], PNPLA3 [270], CPB2 [271], SEMA4C [272], LRP2 [273], SLC5A11 [274], F11 [275], ANGPTL2 [276] and CYP2A6 [277] genes might be related to the pathophysiology of autoimmune disease. A recent study revealed that SLAMF7 [278], FCRL3 [279], CCR4 [280], GZMA (granzyme A) [281], CCR2 [282], CD48 [283], CD3E [284], CCL4 [285], FASLG (Fas ligand) [286], SLAMF1 [287], CD28 [288], IL7R [289], UBASH3A [290], CD3D [291], ICOS (inducible T cell costimulator) [292], CCL5 [293], CCL3 [294], LTF (lactotransferrin) [295], CTLA4 [296], TNFRSF9 [253], C6 [297], IL5RA [298], IL2RG [299], NPY2R [300], DRD3 [301], CD52 [302], CD163 [303], IQGAP2 [304], PRPH (peripherin) [305], MSR1 [306], HGF (hepatocyte growth factor) [307] [318], HSD17B3 [319], GREM1 [320], ATF3 [321], HK2 [322], TF (transferrin) [323], GLUL (glutamate-ammonia ligase) [324], DMRT2 [325], FN3K [326], TREH (trehalase) [327], ADAMTS4 [328], BMP2…”

Section: Discussionmentioning

confidence: 99%

“…SLAMF7 [226], GPR174 [227], FCRL3 [228], SLAMF6 [229], EOMES (eomesodermin) [230], CCR4 [231], CCR2 [232], CD48 [233], CD3E [234], CCL26 [235], CCL4 [236], SLAMF1 [237], CD24 [238], IKZF3 [239], CD2 [240], CD28 [241], IL7R [242], FCGR2B [243], UBASH3A [244], CD1C [245], ICOS (inducible T cell costimulator) [246], CD3G [247], CCL3 [248], LTF (lactotransferrin) [249], GPNMB (glycoprotein nmb) [250], CTLA4 [251], IRF4 [252], TNFRSF9 [253], FCRL5 [254], LAIR2 [255], TAB2 [256], CD52 [257], CD163 [258], MSR1 [259], HGF (hepatocyte growth factor) [260], SIGLEC1 [261], TTR (transthyretin) [262], IL24 [263], IL9 [264], CHI3L1 [265], CDH1 [266], OLIG2 [267], NKX6-2 [268]. HK2 [269], PNPLA3 [270], CPB2 [271], SEMA4C [272], LRP2 [273], SLC5A11 [274], F11 [275], ANGPTL2 [276] and CYP2A6 [277] genes might be related to the pathophysiology of autoimmune disease. A recent study revealed that SLAMF7 [278], FCRL3 [279], CCR4 [280], GZMA (granzyme A) [281], CCR2 [282], CD48 [283], CD3E [284], CCL4 [285], FASLG (Fas ligand) [286], SLAMF1 [287], CD28 [288], IL7R [289], UBASH3A [290], CD3D [291], ICOS (inducible T cell costimulator) [292], CCL5 [293], CCL3 [294], LTF (lactotransferrin) [295], CTLA4 [296], TNFRSF9 [253], C6 [297], IL5RA [298], IL2RG […”

Section: Discussionmentioning

confidence: 99%

“…The abnormal expression of CCL18 [206], EOMES (eomesodermin) [207], GZMA (granzyme A) [ [259], HGF (hepatocyte growth factor) [260], SIGLEC1 [261], TTR (transthyretin) [262], IL24 [263], IL9 [264], CHI3L1 [265], CDH1 [266], OLIG2 [267], NKX6-2 [268]. HK2 [269], PNPLA3 [270], CPB2 [271], SEMA4C [272], LRP2 [273], SLC5A11 [274], F11 [275], ANGPTL2 [276] and CYP2A6 [277] genes might be related to the pathophysiology of autoimmune disease. A recent study revealed that SLAMF7 [278], FCRL3 [279], CCR4 [280], GZMA (granzyme A) [281], CCR2 [282] IL2RG [299], NPY2R [300], DRD3 [301], CD52 [302], CD163 [303], IQGAP2 [304], PRPH (peripherin) [305], MSR1 [306], HGF (hepatocyte growth factor) [307], TTR (transthyretin) [308], IL9 [309], ADM (adrenomedullin) [310], ANGPTL4 [311], CHI3L1 [312], CDH1 [313], SREBF1 [314], CDKN1C [315], TSC22D4 [316], CFTR (CF transmembrane conductance regulator) [317], INSIG1 [318], HSD17B3 [319], GREM1 [320], ATF3 [321], HK2 [322], TF (transferrin) [323], GLUL (glutamate-ammonia ligase) [324]<...…”

Section: Construction Of the Tf-hub Gene Regulatory Networkmentioning

confidence: 99%

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Multiple sclerosis (MS) is the main reason for disability caused by autoimmunity. However, effective biomarkers for MS have not been identified. This study explored the molecular mechanisms and potential therapeutic targets for MS occurrence and progression using bioinformatics and next generation sequencing (NGS) data analysis. NGS data GSE138614, including patients with MS and 25 normal control samples, were obtained from Gene Expression Omnibus (GEO) database Differentially expressed genes (DEGs) were filtered and subjected to gene ontology (GO) and pathway enrichment analyses. Protein–protein interaction (PPI) network and module analyses were performed based on the DEGs. MiRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were built by Cytoscape to predict the underlying microRNAs (miRNAs) and transcription factors (TFs) associated with hub genes. We also validated the identified hub genes via receiver operating characteristic (ROC) curve analysis. A total of 959 DEGs (479 up regulated genes and 480 down regulated genes) were detected. The GO terms and pathways of DEGs involve immune system process, developmental process, immune system and regulation of cholesterol biosynthesis by SREBP (SREBF). The network analysis revealed that hub genes include LCK, PYHIN1, SLAMF1, DOK2, TAB2, CFTR, RHOB, LMNA, EGLN3 and ERBB3 might be involved in the development of MS. The present investigation illustrates a characteristic gene profile in MS, which might contribute to the interpretation of the progression of MS and provide novel biomarkers and therapeutic targets for MS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Construction Of the Tf-hub Gene Regulatory Networkmentioning

confidence: 99%

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“…The activation of T cell functions by ICIs can lead to a series of inflammatory adverse events, the precise pathophysiological mechanisms of which are not fully understood [ 124 ]. Current understanding suggests that immune-related adverse events (irAEs) may arise through various pathways involving autoreactive T cells, autoantibodies, and cytokines [ 125 ].…”

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Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy

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“…In addition, mice overexpressing Angptl2 in cardiomyocytes exhibited cardiac dysfunction with lower contractility and lower myocardial energy metabolism, while loss of cardiomyocyte-derived Angptl2 was protective and restored cardiac function ( Tian et al, 2016 ). In murine models of cardiac injury induced by immunotherapy ( Horiguchi et al, 2023 ), septic shock ( Li et al, 2023 ) or the chemotherapeutic drug doxorubicin ( Liu et al, 2022 ), overexpression of ANGPTL2 aggravated cardiac dysfunction and inflammation. ANGPTL2 derived from epicardial adipose tissue could also be involved in fibrotic remodeling of the heart, a substrate for atrial fibrillation ( Abe et al, 2018 ; Kira et al, 2020 ; Takahashi et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of ANGPTL2 promotes left ventricular systolic dysfunction by upregulation of NOX4 in mice

Labbé,

Martel,

Shi

et al. 2024

Front. Physiol.

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Background: Angiopoietin-like 2 (ANGPTL2) is a pro-inflammatory and pro-oxidant circulating protein that predicts and promotes chronic inflammatory diseases such as atherosclerosis in humans. Transgenic murine models demonstrated the deleterious role of ANGPTL2 in vascular diseases, while deletion of ANGPTL2 was protective. The nature of its role in cardiac tissues is, however, less clear. Indeed, in adult mice knocked down (KD) for ANGPTL2, we recently reported a mild left ventricular (LV) dysfunction originating from a congenital aortic valve stenosis, demonstrating that ANGPTL2 is essential to cardiac development and function.Hypothesis: Because we originally demonstrated that the KD of ANGPTL2 protected vascular endothelial function via an upregulation of arterial NOX4, promoting the beneficial production of dilatory H2O2, we tested the hypothesis that increased cardiac NOX4 could negatively affect cardiac redox and remodeling and contribute to LV dysfunction observed in adult Angptl2-KD mice.Methods and results: Cardiac expression and activity of NOX4 were higher in KD mice, promoting higher levels of cardiac H2O2 when compared to wild-type (WT) mice. Immunofluorescence showed that ANGPTL2 and NOX4 were co-expressed in cardiac cells from WT mice and both proteins co-immunoprecipitated in HEK293 cells, suggesting that ANGPTL2 and NOX4 physically interact. Pressure overload induced by transverse aortic constriction surgery (TAC) promoted LV systolic dysfunction in WT mice but did not further exacerbate the dysfunction in KD mice. Importantly, the severity of LV systolic dysfunction in KD mice (TAC and control SHAM) correlated with cardiac Nox4 expression. Injection of an adeno-associated virus (AAV9) delivering shRNA targeting cardiac Nox4 expression fully reversed LV systolic dysfunction in KD-SHAM mice, demonstrating the causal role of NOX4 in cardiac dysfunction in KD mice. Targeting cardiac Nox4 expression in KD mice also induced an antioxidant response characterized by increased expression of NRF2/KEAP1 and catalase.Conclusion: Together, these data reveal that the absence of ANGPTL2 induces an upregulation of cardiac NOX4 that contributes to oxidative stress and LV dysfunction. By interacting and repressing cardiac NOX4, ANGPTL2 could play a new beneficial role in the maintenance of cardiac redox homeostasis and function.

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ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis

Cited by 3 publications

References 53 publications

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy

Knockdown of ANGPTL2 promotes left ventricular systolic dysfunction by upregulation of NOX4 in mice

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