Dataset Information

Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy.

ABSTRACT:

Aims

Doxorubicin is used in classical chemotherapy for several cancer types. Doxorubicin-induced cardiomyopathy (DOX-CM) is a critical issue among cancer patients. However, differentiating the diagnosis of DOX-CM from that of other cardiomyopathies is difficult. Therefore, in this study, we aimed to determine novel histopathological characteristics to diagnose DOX-CM.

Methods and results

Twelve consecutive patients with DOX-CM who underwent cardiac histopathological examination in two medical centres were included. Twelve patients with dilated cardiomyopathy, who were matched with DOX-CM patients in terms of age, sex, and left ventricular ejection fraction, formed the control group. Another control group comprised five consecutive patients with cancer therapy-related cardiac dysfunction induced by tyrosine kinase inhibitors or vascular endothelial growth factor inhibitors were the controls. The positive area of tenascin-C, number of infiltrating macrophages, and presence of p62- and ubiquitin-positive cardiomyocytes were evaluated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used for in vitro investigation. The myocardium exhibited significantly greater tenascin-C-positive area and macrophage number in the DOX-CM group than in the control groups (P < 0.01). The tenascin-C-positive area correlated with the number of both CD68- and CD163-positive cells (r = 0.748 and r = 0.656, respectively). Immunostaining for p62 was positive in 10 (83%) patients with DOX-CM. Furthermore, western blotting analysis revealed significant increase in tenascin-C levels in hiPSC-CMs upon doxorubicin treatment (P < 0.05).

Conclusion

The combined histopathological assessment for tenascin-C, macrophages, and p62/ubiquitin may serve as a novel tool for the diagnosis of DOX-CM. Doxorubicin may directly affect the expression of tenascin-C in the myocardium.

SUBMITTER: Nishikawa T

PROVIDER: S-EPMC10613965 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy.

Nishikawa Tatsuya T Shiba Mikio M Ikeda Yoshihiko Y Ohta-Ogo Keiko K Kondo Takumi T Tabata Tomoka T Oka Toru T Shioyama Wataru W Yamamoto Hironori H Yasui Taku T Higuchi Yoshiharu Y Ishibashi-Ueda Hatsue H Honma Keiichiro K Izumi Chisato C Higo Shuichiro S Hatakeyama Kinta K Sakata Yasushi Y Fujita Masashi M

European heart journal open 20230901 5

<h4>Aims</h4>Doxorubicin is used in classical chemotherapy for several cancer types. Doxorubicin-induced cardiomyopathy (DOX-CM) is a critical issue among cancer patients. However, differentiating the diagnosis of DOX-CM from that of other cardiomyopathies is difficult. Therefore, in this study, we aimed to determine novel histopathological characteristics to diagnose DOX-CM.<h4>Methods and results</h4>Twelve consecutive patients with DOX-CM who underwent cardiac histopathological examination in ...[more]

PMID: 37908440

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Project description:BACKGROUND: Doxorubicin (DOX) stimulates excessive oxidative stress and dose-dependent cardiotoxicity that exacerbate cardiac dysfunction with complex progression, which DOX-induced cardiomyopathy (DIC) becomes a classical heart failure model to investigate the mechanism or treatment of heart failure. Phosphatase 6 Regulatory Subunit 2 (PPP6R2) is high expression in human heart and mainly involved in the opposing of NF-κB. Isoquercitrin (IQ) is an antioxidant and anti-inflammatory flavonoid found in medicinal herbs. However, the function of PPP6R2 has not been defined. This study aims to elucidate the effects and mechanisms of PPP6R2 on heart failure and the role of IQ in the procession. METHODS: The protective phenotype and function of IQ were evaluated in myocardium through fluorescence and Western blot assays. TMT labeled proteomics analysis was performed to identify the target proteins in a myocardium model induced by AAPH and Dox. The PPP6R2a and PPP6R2b crispants of zebrafish were generated using the CRISPR/Cas9 technique. ShRNA sequences targeting nucleotide sites of rat PPP6R2 and Protein Phosphatase 6 Catalytic Subunit (PPP6C) mRNA were designed, synthesized, and inserted PPP6R2 and PPP6C shRNA sequences to construct PPP6R2-KD and PPP6C-KD plasmid. PPP6R2-KD and PPP6C-KD lentivirus was produced through PPP6R2-KD and PPP6C-KD plasmid transfection into H9c2 cells together with the packaging plasmids. Furthermore, the immunoprecipitation, mass spectrometry analysis, and IQ-based hydrogel development that was followed by multiple molecular biological methodologies to prove the key function of target PPP6R2 in regulating the procession of heart failure. RESULTS: It is observed that IQ alleviates myocardial damage and dysfunction by reducing DOX-induced oxidative stress and maintaining mitochondrial homeostasis. Subsequently, the molecular target of IQ through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, IQ physically binds to and promotes the expression of the PPP6R2 content. In addition, it was observed that PPP6R2 bind to PPP6C, ultimately inhibiting NF-κB p65 and subsequent alleviated peroxidation. Given the critical role of PPP6R2 in the pathogenesis of DIC injury, this further investigation posits that IQ-based hydrogel deliver IQ in DIC, thereby reconciling the inflammatory response, enhancing cardiomyocyte survival, and optimizing functional phenotype. CONCLUSIONS: Overall, a novel progression pathway targeting PPP6R2/PPP6C/NF-κB axis in DIC and a pharmacological inhibitor were unveiled that targets oxidative stress and inflammatory, presenting a therapeutic avenue for DIC treatment.

Dataset Information

Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy.

Aims

Methods and results

Conclusion

Publications

Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy.

Similar Datasets

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