PXD043577

PXD043577 is an original dataset announced via ProteomeXchange.

Title	Myofibroblast-specific Smad7 protects the pressure-overloaded heart by restraining collagen deposition and denaturation, and by inhibiting paracrine macrophage activation
Description	Rationale: Expansion and activation of cardiac fibroblasts contributes to adverse remodeling, fibrosis and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β/Smad3 activation protects the pressure overloaded heart by preserving the matrix, sustained TGF-β activation may be deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF- response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. Objective: To study the role of fibroblast-specific induction of Smad7, an inhibitory Smad that restrains TGF-β signaling, in regulation of fibrosis, remodeling and dysfunction of the pressure-overloaded heart. Methods and Results: In a mouse model of pressure overload induced through transverse aortic constriction (TAC), Smad7 was upregulated in cardiac fibroblasts and myofibroblasts. Mice with myofibroblast-specific loss of Smad7 (MFS7KO) had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to TAC. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased collagen denaturation, in the absence of effects on cardiomyocyte death. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins, and markedly increases secretion of matrix metalloproteinase-2 (MMP2). In a 3D model of fibroblasts populating collagen lattices the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Secretomic analysis and in vitro experiments suggested that macrophage activation involves the combined effects of the fibroblast-derived matricellular proteins CD5L, SPARC, CTGF, ECM1 and TGFBI. Conclusions: The anti-fibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition, but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.
HostingRepository	PRIDE
AnnounceDate	2025-07-28
AnnouncementXML	Submission_2025-07-27_16:13:53.053.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simone Sidoli
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	2023-07-06 01:26:38	ID requested
⏵ 1	2025-07-27 16:13:53	announced

10.1161/circresaha.123.323360;

Humeres C, Shinde AV, Tuleta I, Hernandez SC, Hanna A, Huang S, Venugopal H, Aguilan JT, Conway SJ, Sidoli S, Frangogiannis NG, Fibroblast Smad7 Induction Protects the Remodeling Pressure-Overloaded Heart. Circ Res, 135(3):453-469(2024) [pubmed]

submitter keyword: heart, tgf-beta, fibrosis,smad7

Simone Sidoli
contact affiliation	Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
contact email	simone.sidoli@einsteinmed.edu
lab head
Simone Sidoli
contact affiliation	Albert Einstein College of Medicine
contact email	simone.sidoli@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043577
     1. Label: PRIDE project
     2. Name: Myofibroblast-specific Smad7 protects the pressure-overloaded heart by restraining collagen deposition and denaturation, and by inhibiting paracrine macrophage activation