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

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 PDGFR beta in fibroblasts. This was not due to the reduced PDGFR beta expression levels or decreased binding of the PDGF ligand to PDGFR beta. SPRR3 facilitated the association of integrin beta 1 with PDGFR beta and subsequently fibroblast proliferation, suggesting a role in PDGFR beta-Integrin synergy. We postulate that SPRR3 may function as a conduit for the coordinated activation of PDGFR beta by integrin beta 1, leading to augmentation of fibroblast proliferation and matrix synthesis downstream of biomechanical and growth factor signals.