PXD056266

PXD056266 is an original dataset announced via ProteomeXchange.

Title	A PPP6R2 promoter, isoquercitrin, alleviate doxorubicin-induced cardiomyopathy
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.
HostingRepository	iProX
AnnounceDate	2024-09-26
AnnouncementXML	Submission_2024-09-25_20:11:06.212.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yulin Dai
SpeciesList	scientific name: Rattus norvegicus; NCBI TaxID: 10116;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-25 20:10:46	ID requested
⏵ 1	2024-09-25 20:11:06	announced

Dataset with its publication pending

submitter keyword: PPP6R2, isoquercitrin, doxorubicin-induced cardiomyopathy, PPP6C

Yulin Dai
contact affiliation	Changchun University of Chinese Medicine
contact email	daiyl@ccucm.edu.cn
lab head
Yulin Dai
contact affiliation	Changchun University of Chinese Medicine
contact email	daiyl@ccucm.edu.cn
dataset submitter

iProX dataset URI