Small proline‐rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts

Autor: Pampee P. Young, Bin Li, Roy Zent, Caressa Lietman, Sarika Saraswati, Sijo Mathew
Rok vydání: 2020
Předmět:
collagen
Male
0301 basic medicine
MAPK/ERK pathway
medicine.medical_treatment
Myocytes
Smooth Muscle
Integrin
heart failure
Biochemistry
Receptor
Platelet-Derived Growth Factor beta
Mice
03 medical and health sciences
0302 clinical medicine
transverse aortic constriction
Cornified Envelope Proline-Rich Proteins
Cell Adhesion
Genetics
medicine
Animals
Cell adhesion
Fibroblast
Molecular Biology
Protein kinase B
Research Articles
Cell Proliferation
biology
Chemistry
Integrin beta1
Myocardium
Growth factor
fibrosis
Heart
pressure overload
Fibroblasts
Cell biology
Mice
Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
biology.protein
Signal transduction
030217 neurology & neurosurgery
Platelet-derived growth factor receptor
Research Article
Signal Transduction
Biotechnology
Zdroj: The FASEB Journal
ISSN: 1530-6860
0892-6638
Popis: Nearly 6 million Americans suffer from heart failure. Increased fibrosis contributes to functional decline of the heart that leads to heart failure. Previously, we identified a mechanosensitive protein, small proline‐rich repeat 3 (SPRR3), in vascular smooth muscle cells of atheromas. In this study, we demonstrate SPRR3 expression in cardiac fibroblasts which is induced in activated fibroblasts following pressure‐induced heart failure. Sprr3 deletion in mice showed preserved cardiac function and reduced interstitial fibrosis in vivo and reduced fibroblast proliferation and collagen expression in vitro. SPRR3 loss resulted in reduced activation of Akt, FAK, ERK, and p38 signaling pathways, which are coordinately regulated by integrins and growth factors. SPRR3 deletion did not impede integrin‐associated functions including cell adhesion, migration, or contraction. SPRR3 loss resulted in reduced activation of PDGFRβ in fibroblasts. This was not due to the reduced PDGFRβ expression levels or decreased binding of the PDGF ligand to PDGFRβ. SPRR3 facilitated the association of integrin β1 with PDGFRβ and subsequently fibroblast proliferation, suggesting a role in PDGFRβ‐Integrin synergy. We postulate that SPRR3 may function as a conduit for the coordinated activation of PDGFRβ by integrin β1, leading to augmentation of fibroblast proliferation and matrix synthesis downstream of biomechanical and growth factor signals.
Databáze: OpenAIRE
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