Abstract
Periostin (PN), a novel fasciclin-related matricellular protein, has been implicated in cardiac development and postnatal remodeling, but the mechanism remains unknown. We examined the role of PN in mediating intracellular kinase activation for atrioventricular valve morphogenesis using well defined explant cultures, gene transfection systems, and Western blotting. The results show that valve progenitor (cushion) cells secrete PN into the extracellular matrix, where it can bind to INTEGRINs and activate INTEGRIN/focal adhesion kinase signaling pathways and downstream kinases, PI3K/AKT and ERK. Functional assays with prevalvular progenitor cells showed that activating these signaling pathways promoted adhesion, migration, and anti-apoptosis. Through activation of PI3K/ERK, PN directly enhanced collagen expression. Comparing PN-null to WT mice also revealed that expression of hyaluronan (HA) and activation of hyaluronan synthase-2 (Has2) are also enhanced upon PN/INTEGRIN/focal adhesion kinase-mediated activation of PI3K and/or ERK, an effect confirmed by the reduction of HA synthase-2 in PN-null mice. We also identified in valve progenitor cells a potential autocrine signaling feedback loop between PN and HA through PI3K and/or ERK. Finally, in a three-dimensional assay to simulate normal valve maturation in vitro, PN promoted collagen compaction in a kinase-dependent fashion. In summary, this study provides the first direct evidence that PN can act to stimulate a valvulogenic signaling pathway.
Highlights
Periostin-null mice exhibit a myxomatous atrioventricular valve phenotype
Summary—The results presented in this study provide a more comprehensive picture of the role of PN in valve morphogenesis by testing the hypothesis that PN secreted by developing valve progenitor cells induces signaling pathways that change biological functions related to morphogenesis via binding to cell-surface receptors, 3- and 1-INTEGRINs
The interaction between PN and -INTEGRINs was found to activate FAK and downstream PI3K and MAPK pathways that lead to the phosphorylation of AKT and ERK, factors that are well known for their effects upon survival, adhesion/migration, and collagen synthesis
Summary
We propose two mechanisms as follows: periostin binds to collagen and links it to cell-surface receptors; periostin/-INTEGRIN signaling promotes valve morphogenesis. Results: Periostin/-INTEGRINs/focal adhesion kinase/PI3K/ERK signals promote hyaluronan synthase-2 activation, matrix remodeling, and valve progenitor cell survival/differentiation. Conclusion: The phenotype of periostin-null valves is consistent with a role for PN cell signaling through INTEGRIN receptors. The results show that valve progenitor (cushion) cells secrete PN into the extracellular matrix, where it can bind to INTEGRINs and activate INTEGRIN/focal adhesion kinase signaling pathways and downstream kinases, PI3K/AKT and ERK. Comparing PN-null to WT mice revealed that expression of hyaluronan (HA) and activation of hyaluronan synthase-2 (Has2) are enhanced upon PN/INTEGRIN/focal adhesion kinase-mediated activation of PI3K and/or ERK, an effect confirmed by the reduction of HA synthase-2 in PN-null mice. In a three-dimensional assay to simulate normal valve maturation in vitro, PN promoted collagen compaction in a kinase-dependent
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