PXD050300

PXD050300 is an original dataset announced via ProteomeXchange.

Title	Cardiac Fibroblast Foxm1 Deficiency Prevents Pressure Overload-Induced Cardiac Remodeling via the Usp10/p38γ MAPK Axis
Description	Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus influencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.
HostingRepository	PRIDE
AnnounceDate	2024-03-10
AnnouncementXML	Submission_2024-03-09_18:42:44.090.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	fengze cai
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-03 21:00:40	ID requested
⏵ 1	2024-03-09 18:42:44	announced

Dataset with its publication pending

submitter keyword: Heart Failure, Cardiac Remodelling, Fibroblast,Foxm1

shuai song
contact affiliation	Department of Cardiology, Zhongshan Hospital, Fudan University
contact email	20111210036@fudan.edu.cn
lab head
fengze cai
contact affiliation	Zhongshan Hospital, Fudan University
contact email	2623020892@qq.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/03/PXD050300

PRIDE project URI

• PRIDE
  1. PXD050300
     1. Label: PRIDE project
     2. Name: Cardiac Fibroblast Foxm1 Deficiency Prevents Pressure Overload-Induced Cardiac Remodeling via the Usp10/p38γ MAPK Axis