Abstract
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.
Highlights
The family of tissue inhibitor of metalloproteinases (TIMPs) is composed of 4 members, TIMP1 to TIMP4, which are the physiological inhibitors of matrix metalloproteinases (MMPs)
Tissue inhibitor of metalloproteinase 3 (TIMP3) is unique among the four TIMPs because it is the only one with a high affinity for the proteoglycans in the extracellular matrix (ECM), as well as its broadest range of substrates, including all MMPs, and a number of a disintegrin and metalloproteinases (ADAMs) and ADAMTSs (ADAM with thrombospondin motifs) (Staskus et al, 1991; Pavloff et al, 1992; Leco et al, 1994; Apte et al, 1995; Brew and Nagase, 2010; Moore et al, 2012; Jackson et al, 2017)
TIMP3 Biochemistry and Cardiovascular Diseases of reports show that TIMPs have more diverse functions beyond MMP inhibition
Summary
The family of tissue inhibitor of metalloproteinases (TIMPs) is composed of 4 members, TIMP1 to TIMP4, which are the physiological inhibitors of matrix metalloproteinases (MMPs). Among the four TIMPs, Timp has the longest 3’ untranslated region (UTR) contained in the exon 5 (Leco et al, 1994; Apte et al, 1995), which is a target for multiple microRNAs. MicroRNAs (miRNA, miR) are a group of short, non-coding RNAs with 18−25 bases which can regulate gene expression at the transcriptional and post-transcriptional stages (Mohr and Mott, 2015; Dutka et al, 2019; Yao et al, 2019). MiR181b targets Timp and reduces apoptosis of cardiomyocytes (Gao et al, 2017), but enhances gelatinases/MMP activity in human aortic valve endothelial cells which may contribute to calcific aortic valve disease (Heath et al, 2018). With the widest inhibitory spectrum against metalloproteinases, TIMP3 can suppress all MMPs, a number of ADAMs
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