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?IV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function.


ABSTRACT: Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress and a determinant of cardiac mechanical and electrical dysfunction in disease. Stress-induced activation of cardiac fibroblasts (CFs) is a critical step in the fibrotic response, although the precise sequence of events underlying activation of these critical cells in vivo remain unclear. Here, we tested the hypothesis that a ?IV-spectrin/STAT3 complex is essential for maintenance of a quiescent phenotype (basal nonactivated state) in CFs. We reported increased fibrosis, decreased cardiac function, and electrical impulse conduction defects in genetic and acquired mouse models of ?IV-spectrin deficiency. Loss of ?IV-spectrin function promoted STAT3 nuclear accumulation and transcriptional activity, and it altered gene expression and CF activation. Furthermore, we demonstrate that a quiescent phenotype may be restored in ?IV-spectrin-deficient fibroblasts by expressing a ?IV-spectrin fragment including the STAT3-binding domain or through pharmacological STAT3 inhibition. We found that in vivo STAT3 inhibition abrogates fibrosis and cardiac dysfunction in the setting of global ?IV-spectrin deficiency. Finally, we demonstrate that fibroblast-specific deletion of ?IV-spectrin is sufficient to induce fibrosis and decreased cardiac function. We propose that the ?IV-spectrin/STAT3 complex is a determinant of fibroblast phenotype and fibrosis, with implications for remodeling response in cardiovascular disease (CVD).

SUBMITTER: Patel NJ 

PROVIDER: S-EPMC6824442 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress and a determinant of cardiac mechanical and electrical dysfunction in disease. Stress-induced activation of cardiac fibroblasts (CFs) is a critical step in the fibrotic response, although the precise sequence of events underlying activation of these critical cells in vivo remain unclear. Here, we tested the hypothesis that a βIV-spectrin/STAT3 complex is essential for maintenance of a quiescent ph  ...[more]

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