Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature

Abstract

Matrix metalloproteinases (MMPs) have been shown to play significant roles in a number of physiological as well as pathological processes. Best known to proteolyse components of the extracellular matrix, MMPs have recently been discovered to also target a growing list of proteins apart from these, both inside and outside the cell. MMPs have also been traditionally thought of as enzymes involved in chronic processes such as angiogenesis, remodelling and atherosclerosis on a days-week time-scale. However they are now understood to also act acutely in response to oxidative stress on a minutes time-scale on non-extracellular matrix substrates. This review focuses on the acute actions and both extracellular and intracellular targets of two prominent MMP family members, MMP-2 and -9, in cardiovascular diseases including ischaemia/reperfusion injury, inflammatory heart disease, septic shock and pre-eclampsia. Also discussed are various ways of regulating MMP activity, including post-translational mechanisms, the endogenous tissue inhibitors of metalloproteinases and pharmacological inhibitors. A comprehensive understanding of MMP biology is necessary for the development of novel pharmacological therapies to combat the impact of cardiovascular disease.

Figure 1

MMP structure. MMPs are typically classified according to the substrates they degrade and possess several general common structural characteristics. The N-terminal domain typically contains a signalling sequence, which allows for the extracellular export of the enzyme. All MMPs are produced in a zymogen form with a propeptide domain that contains a cysteine switch. The catalytic domain of all MMPs contain a Zn²⁺ ion. The catalytic domain of the gelatinases (MMP-2 and -9) is unique in that it contains three fibronectin repeats. Apart from the matrilysins (MMP-7 an -26), MMPs contain a flexible hinge region which also has a haemopexin domain linked to a C-terminal tail. MMP, matrix metalloproteinase; MT-MMP, membrane-type matrix metalloproteinase.

Figure 2

Activation mechanisms of MMP-2. The full-length MMP-2 can be activated in two ways. Proteolytic activation of MMP-2 by MT1-MMP/TIMP or by other proteases occurs by removal of the autoinhibitory propeptide domain (left arrow) resulting in an active truncated MMP-2. The presence of oxidative stress (ONOO⁻) and cellular glutathione (GSH) causes the S-gluathiolation of the critical cysteine residue in the propeptide domain, disrupting its binding to the catalytic Zn²⁺ ion, resulting in an active full-length enzyme. MMP, matrix metalloproteinase; ONOO⁻, peroxynitrite; TIMP, tissue inhibitor of metalloproteinase.

Figure 3

Targets of MMP-2 in the heart following I/R injury. Extracellular targets of MMP-2 may include matrix proteins such as laminin, elastin, type IV collagen and fibronectin. This may lead to a disruption in cell–cell adhesion and communication. This likely occurs only after severe ischaemia resulting in infarct and remodelling processes, which occur on a days–weeks time-scale. Within the cardiomyocyte (right), MMP-2, which is activated as a result of oxidative stress, can rapidly cleave sarcomeric proteins such as TnI and MLC-1 to cause acute contractile dysfunction on a seconds–minutes time-scale following I/R injury. I/R, ischaemia and reperfusion; MLC-1, myosin light chain-1; MMP, matrix metalloproteinase.

Figure 4

Proteolytic regulation of vascular tone by MMP-2. MMP-2 can regulate vascular tone via proteolysis of vasoactive peptides. Left: MMP-2 cleaves Big ET-1 to yield a potent vasoconstrictor, Med ET-1. Centre: MMP-2 can also proteolyse the vasodilatory peptide adrenomedullin resulting in the generation of both vasoconstrictor and vasodilator peptides. Right: MMP-2 is also able to cleave CGRP to non-vasoactive degradation products, thus inactivating its vasodilatory activity. CGRP, calcitonin gene-related peptide; big ET-1, big endothelin-1; MED et-1, medium endothelin-1; MMP, matrix metalloproteinase.