1. Entanglement of GSK-3β, β-catenin and TGF-β1 signaling network to regulate myocardial fibrosis.
- Author
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Guo, Yuanjun, Gupte, Manisha, Umbarkar, Prachi, Singh, Anand Prakash, Sui, Jennifer Y., Force, Thomas, and Lal, Hind
- Subjects
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MYOCARDIAL infarction , *HEART diseases , *PHENOTYPES , *FIBROSIS , *EXTRACELLULAR matrix - Abstract
Nearly every form of the heart disease is associated with myocardial fibrosis, which is characterized by the accumulation of activated cardiac fibroblasts (CFs) and excess deposition of extracellular matrix (ECM). Although, CFs are the primary mediators of myocardial fibrosis in a diseased heart, in the traditional view, activated CFs (myofibroblasts) and resulting fibrosis were simply considered the secondary consequence of the disease, not the cause. Recent studies from our lab and others have challenged this concept by demonstrating that fibroblast activation and fibrosis are not simply the secondary consequence of a diseased heart, but are crucial for mediating various myocardial disease processes. In regards to the mechanism, the vast majority of literature is focused on the direct role of canonical SMAD-2/3-mediated TGF-β signaling to govern the fibrogenic process. Herein, we will discuss the emerging role of the GSK-3β, β-catenin and TGF-β1-SMAD-3 signaling network as a critical regulator of myocardial fibrosis in the diseased heart. The underlying molecular interactions and cross-talk among signaling pathways will be discussed. We will primarily focus on recent in vivo reports demonstrating that CF-specific genetic manipulation can lead to aberrant myocardial fibrosis and sturdy cardiac phenotype. This will allow for a better understanding of the driving role of CFs in the myocardial disease process. We will also review the specificity and limitations of the currently available genetic tools used to study myocardial fibrosis and its associated mechanisms. A better understanding of the GSK-3β, β-catenin and SMAD-3 signaling network may provide a novel therapeutic target for the management of myocardial fibrosis in the diseased heart. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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