Dataset Information

PKC-ζ Aggravates Doxorubicin-Induced Cardiotoxicity by Inhibiting Wnt/β-Catenin Signaling.

ABSTRACT: Doxorubicin (Dox) is a chemotherapeutic drug used to treat a wide range of cancers, but its clinical application is limited due to its cardiotoxicity. Protein kinase C-ζ (PKC-ζ) is a serine/threonine kinase belonging to atypical protein kinase C (PKC) subfamily, and is activated by its phosphorylation. We and others have reported that PKC-ζ induced cardiac hypertrophy by activating the inflammatory signaling pathway. This study focused on whether PKC-ζ played an important role in Dox-induced cardiotoxicity. We found that PKC-ζ phosphorylation was increased by Dox treatment in vivo and in vitro. PKC-ζ overexpression exacerbated Dox-induced cardiotoxicity. Conversely, knockdown of PKC-ζ by siRNA relieved Dox-induced cardiotoxicity. Similar results were observed when PKC-ζ enzyme activity was inhibited by its pseudosubstrate inhibitor, Myristoylated. PKC-ζ interacted with β-catenin and inhibited Wnt/β-catenin signaling pathway. Activation of Wnt/β-catenin signaling by LiCl protected against Dox-induced cardiotoxicity. The Wnt/β-catenin inhibitor XAV-939 aggravated Dox-caused decline of β-catenin and cardiomyocyte apoptosis and mitochondrial damage. Moreover, activation of Wnt/β-catenin suppressed aggravation of Dox-induced cardiotoxicity due to PKC-ζ overexpression. Taken together, our study revealed that inhibition of PKC-ζ activity was a potential cardioprotective approach to preventing Dox-induced cardiac injury.

SUBMITTER: Cao YJ

PROVIDER: S-EPMC8883055 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PKC-ζ Aggravates Doxorubicin-Induced Cardiotoxicity by Inhibiting Wnt/β-Catenin Signaling.

Cao Yan-Jun YJ Li Jing-Yan JY Wang Pan-Xia PX Lin Zhi-Rong ZR Yu Wen-Jing WJ Zhang Ji-Guo JG Lu Jing J Liu Pei-Qing PQ

Frontiers in pharmacology 20220214

Doxorubicin (Dox) is a chemotherapeutic drug used to treat a wide range of cancers, but its clinical application is limited due to its cardiotoxicity. Protein kinase C-ζ (PKC-ζ) is a serine/threonine kinase belonging to atypical protein kinase C (PKC) subfamily, and is activated by its phosphorylation. We and others have reported that PKC-ζ induced cardiac hypertrophy by activating the inflammatory signaling pathway. This study focused on whether PKC-ζ played an important role in Dox-induced car ...[more]

PMID: 35237161

Similar Datasets

Project description:BackgroundThe serum levels of sclerostin (SOST) are significant elevated in patients with pathological cardiac remodeling after myocardial infarction (MI). However, the mechanisms of SOST in cardiac remodeling remain largely uncharacterized.MethodsCollecting patients with MI who presented with or without left ventricular (LV) remodeling, we investigated differences in SOST expression. The influence of overexpression and silenced of SOST on the angiogenesis of cardiac microvascular endothelial cells (CMECs) was explored through in vitro experiments, and the impact of SOST on Wnt signaling marker proteins was examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Finally, we observed the effects of SOST on cardiac function and morphology in mice MI model, and verified the role of the Wnt signaling marker proteins in vivo.ResultsSerum SOST was significantly increased in patients with cardiac remodeling. Increased SOST expression was also observed in the infarcted hearts of C57BL/6 mice that underwent ligation of the left anterior descending branch of the coronary artery to induce MI. Furthermore, loss and gain of function experiments were conducted to investigate the role of SOST in post-infarct cardiac remodeling in vivo and in vitro. Overexpression of SOST promoted the proliferation and migration of cardiac fibroblasts (CFs), and inhibited angiogenesis of CMECs. In addition, overexpressing SOST in mice significantly deteriorated the post-infarct cardiac remodeling, as shown by the increased LV end systolic and end diastolic dimensions, decreased ejection fraction, and increased myocyte cross-section area and myocardial fibrosis. However, suppressing SOST expression showed the opposite results. The expression of Wnt signaling marker proteins was inhibited after overexpression of SOST, and enhanced after suppression of SOST in vivo and in vitro, suggesting involvement of the Wnt signaling pathway.ConclusionsThe present study demonstrated that SOST aggravates post-infarct pathological myocardial remodeling by inhibiting angiogenesis of CMECs while promoting the proliferation of CFs, and this may be mediated by the Wnt signaling pathway. These results suggested that SOST might act as a biomarker to predict detrimental postinfarct cardiac remodeling, and may be a potential therapeutic target for the treatment of MI.

Dataset Information

PKC-ζ Aggravates Doxorubicin-Induced Cardiotoxicity by Inhibiting Wnt/β-Catenin Signaling.

Publications

PKC-ζ Aggravates Doxorubicin-Induced Cardiotoxicity by Inhibiting Wnt/β-Catenin Signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets