Regulation and involvement of matrix metalloproteinases in vascular diseases - PubMed (original) (raw)

Review

. 2016 Jan 1;21(1):89-118.

doi: 10.2741/4378.

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Review

Regulation and involvement of matrix metalloproteinases in vascular diseases

Matthew Amin et al. Front Biosci (Landmark Ed). 2016.

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases whose main function is to degrade and deposit structural proteins within the extracellular matrix (ECM). A dysregulation of MMPs is linked to vascular diseases. MMPs are classified into collagenases, gelatinases, membrane-type, metalloelastase, stromelysins, matrilysins, enamelysins, and unclassified subgroups. The production of MMPs is stimulated by factors such as oxidative stress, growth factors and inflammation which lead to its up- or down-regulation with subsequent ECM remodeling. Normally, excess activation of MMPs is controlled by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). An imbalance of MMPs and TIMPs has been implicated in hypertension, atherosclerotic plaque formation and instability, aortic aneurysms and varicose vein wall remodeling. Also, recent evidence suggests epigenetic regulation of some MMPs in angiogenesis and atherosclerosis. Over the years, pharmacological inhibitors of MMPs have been used to modify or prevent the development of the disease with some success. In this review, we discuss recent advances in MMP biology, and their involvement in the manifestation of vascular disease.

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Figures

Figure 1

Figure 1

Schematic of generalized structure of MMPs. The Prodomain has a cleavage site at RxRRR which activates the subsequent autocatalysis of the pro-enzyme. Although MMP-23 has the cleavage site, it is the only one that lacks a prodomain. The catalytic domain is common across all MMPs consisting of two Zn2+ ions where one is purely structural, while the other is involved in catalytic activity. The catalytic zinc interacts with a cysteine residue (cysteine switch) within the prodomain to remain inactive. The Hemopexin-like domain and catalytic domain are connect by a linker peptide, and is observed at the C-terminus of all MMPs except for MMP-7,-23, and -26. Its sequence homology resembles that of hemopexin, a protein with heme-binding capabilities. It enhances substrate recognition and specificity in stromelysins and collagenases, but not required for elastase activity in metalloelastase. Lastly, TIMP: proenzyme interactions are facilitated by this domain in gelatinases. The Fib1-3s are fibronectin-like type II domains found only in gelatinases.

Figure 2

Figure 2

Subgroup classification of MMPs.

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