Review article
Matrix metalloproteinases in pro-atherosclerotic arterial remodeling

https://doi.org/10.1016/j.yjmcc.2018.08.026Get rights and content

Highlights

  • MMPs are Zn proteases that process the extracellular matrix components

  • MMPs are implicated in numerous human disease, including cancer and atherosclerosis

  • MMPs are involved in all stages of atherosclerotic plaque development, but their roles are not always defined

  • Few MMP inhibitors have been approved so far, but such drugs can prove useful to treat atherosclerosis

  • Novel MMP inhibitors should be selective to target certains MMPs and have better tolerability

Abstract

Matrix metalloproteinases (MMPs) is a family of Zn2+ endopeptidases that process various components of the extracellular matrix. These enzymes are also involved in activation and inhibition of signaling cascades through proteolytic cleavage of surface receptors. Moreover, MMPs play a key role in tissue remodeling and and repair. Dysregulation of MMPs is observed in patholofgical conditions, including atherosclerosis, which is associated with hyperactivation of MMPs, aberrant tissue remodeling and neovascularization of the growing atherosclerotic plaques. This makes MMPs interesting therapeutic targets that can be employed for developing novel therapies to treat atherosclerosis and its complications. Currently, a growing number of synthetic MMP inhibitors is available. In this review, we will discuss the role of these enzymes in atherosclerosis pathology and the ways of their pothential therapeutic use.

Introduction

Matrix metalloproteinases (MMPs) is a family of extracellular zinc proteases that process the protein components of the extracellular matrix (ECM). They are actively involved in tissue repair and remodeling, including vascular remodeling. Cleavage of ECM results in increased migration of cells making the repair processes possible. However, their role is not limited to structural changes of the tissues.

The main components of ECM include elastin, fibronectin, laminin and different types of collagens. Many of the ECM proteins are heavily glycosylated [1]. Proteoglycans that contain many hydroxy groups form a natural reservoir for water and water-soluble molecules, such as polysaccharides and enzymes [2] and various signaling molecules, including growth factors [3] and chemokines [4]. Along with the collagenous and non-collagenous components of ECM, MMPs can process extracellular and cell-surface non-ECM proteins, including receptors, peptide hormones and cytokines, playing therefore a significant signaling role [5]. MMPs can also cleave and activate pro-MMPs [6]. In accordance with their potent effects at the tissue level, MMPs are activated through tightly controlled mechanisms. The activity of MMPs in a given organ is regulated by tissue inhibitors of metalloproteinases (TIMPs) that chelate the catalytic Zn2+ of MMPs (as well as a number of other metalloproteinases) and inactivate the enzymes [7]. The MMP activity in any tissue is dependent on the balance between the activating and inhibiting forces at any given point of time.

Vascular remodeling occurs both in physiological conditions (vascular repair and vasculogenesis) and in cardiovascular pathologies, such as atherosclerosis. It involves decomposition of the ECM and phenotypic changes of the vascular cells, activation of cell proliferation, migration, and at certain point, death [6]. Vascular remodeling is also responsile for controlling the vascular wall thickness [8]. In atherosclerosis, vascular remodeling mediates the intimal thickening that accompanies the lesion formation [9].

In this paper, we will discuss the MMPs functions and significance in physiological and pathological (i.e. atherosclerotic) vascular remodeling, focusing mainly on their effects on the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs).

Section snippets

Nomenclature of MMPs

In humans, 28 members of the MMP family are known, that share an N-terminal propeptide domain, cysteine-containing switch motif Zn2+-containing conservative catalytic domain, C-terminal proline-rich hinge region, and the hemopexin domain (Fig. 1) [6]. The hemopexin repeats and the cysteine switch have regulatory functions, the former being recognized by TIMPs [10], the latter serving as an activator [11].

Generally, the nomenclature of MMPs is based on the substrate precedency and structural

MMP activators

Numerous factors triggering MMP activity are known, including both chemical agents and various physiological and pathological conditions. Like with other enzymes, MMP activity can be controlled at different levels: expression of the MMP genes, proteolytic activation of the proenzymes, inhibition of the catalytic activity by chemical agents or physical sequestration, e.g. in the endosomes. Below, we will mention only some of the described MMP activation factors that may be relevant to

Synthetic inhibitors of MMPs

MMPs have long been regarded as attractive therapeutic targets, and numerous synthetic MMP inhibitors, as well as endogenous inhibitor, such as recombinant TIMPs, have been created and tested in animal models. One of the main challenges in MMP inhibitors development is improving their selectivity towards target MMPs, which would help improving their clinical usefulness and tolerability. Some molecules have made it to early clinical trials, mostly in the oncology field to hamper angiogenesis.

Effects of MMPs on different cell types

It is known that MMPs have profound effects on vascular wall cells, in particular ECs and VSMCs. In the ECs, MMPs were shown to to play an important role, promoting angiogenesis and EC-dependent vasodilation. In rat aorta, increased levels of MMP-2 contribute to endotoxin- or IL-1β-initiated red-uction of EC-dependent response to vasoconstrictor agents [53]. MMP inhibition by doxycycline protected against EC hyporeactivity indicative of a protective role of MMP up-regulation in

Role of MMPs in atherosclerosis

In atherosclerosis, vascular remodeling, which is normally an adaptive response, contributes to the disease development due to pathological conditions established at the lesion sites. ECM remodeling, which is regulated by MMPs, is one of the key characteristics of atherosclerotic process contributing to the plaque growth [74]. Atherosclerotic plaques, and vulnerable plaques in particular, are characterized by increased MMPs expression [75,76]. Exposure of vascular wall cells to inflammatory

Future perspectives

MMPs are tightly involved in physiological and pathological tissue remodeling in atherosclerosis and are considered as potential therapeutic targets. In humans, synthetic MMP inhibitors were clinically tested mainly in cancer and rheumatic patients and exhibited serious adverse effects that limted their application. The development of mechanism-based MMP inhibitors specific to certain MMPs (such as 3B-3CT and derivatives) is a promising strategy to improve therapeutic efficiency of MMP

Conclusions

Accumulating evidence highlights the importance of MMPs at all stages of atherosclerotic lesion development. Accordingly, these enzymes remain attractive therapeutic targets. However, implementation of MMP inhibitors in clinical practice is still restricted due to the unfavourable therapeutic profiles of the existing inhibitors and the need for better understanding of the roles of different MMPs in the plaque iniciation, growth and stabilization. It seems that MMP inhibitors can be more

Funding

This work was supported by Russian Science Foundation (Grant # 18-15-00254).

Conflict of interest

The authors declare no conflict of interest.

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