Journal
FRONTIERS IN PHYSIOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2020.00661
Keywords
tissue inhibitor of metalloproteinases; TIMP3; metalloproteinase; myocardial infarction; cardiovascular diseases; microRNA; extracellular matrix; gene therapy
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Funding
- National Natural Science Foundation of China [81860046]
- Canada Research Chair (Tier 1) in Cardiovascular Extracellular Matrix
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Tissue inhibitor of metalloproteinase 3 (TIMP3) is unique among the four TIMPs due to its extracellular matrix (ECM)-binding property and broad range of inhibitory substrates that includes matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs). In addition to its metalloproteinase-inhibitory function, TIMP3 can interact with proteins in the extracellular space resulting in its multifarious functions. TIMP3 mRNA has a long 3' untranslated region (UTR) which is a target for numerous microRNAs. TIMP3 levels are reduced in various cardiovascular diseases, and studies have shown that TIMP3 replenishment ameliorates the disease, suggesting a therapeutic potential for TIMP3 in cardiovascular diseases. While significant efforts have been made in identifying the effector targets of TIMP3, the regulatory mechanism for the expression of this multi-functional TIMP has been less explored. Here, we provide an overview of TIMP3 gene structure, transcriptional and post-transcriptional regulators (transcription factors and microRNAs), protein structure and partners, its role in cardiovascular pathology and its application as therapy, while also drawing reference from TIMP3 function in other diseases.
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