Matrix metalloproteinases in cardiovascular disease

Abstract

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that are regulated by inflammatory signals to mediate changes in extracellular matrix. Members of the MMP family share sequence homology, act on interstitial protein substrates, acutely participate in inflammatory processes and chronically mediate tissue remodelling. MMPs are important in vascular remodelling, not only in the overall vasculature architecture but also, more importantly, in the advancing atherosclerotic plaque. MMP activation modifies the architecture of the plaque and may directly participate in the process of plaque rupture. MMPs also participate in cardiac remodelling following myocardial infarction and development of dilated cardiomyopathy. Soluble MMPs are now potential biomarkers in delineating cardiovascular risk for plaque rupture and coronary risk. They also constitute innovative direct or indirect targets to modify cardiovascular tissue remodelling in atherosclerosis and heart failure.

Figure 1)

A Three-dimensional rendering of a member of the family of matrix metalloproteinases (MMPs). The catalytic domain contains the active enzymatic site that will bind collagen or gelatin. However, in the proenzyme form, the active site is shielded by a propeptide that is cleavable by free radicals, cytokines or other MMPs to activate the enzyme. The enzyme is stabilized and anchored in some cases through the hemopexin-like and linker domains (Reproduced from reference 2). B Structural relationships of the various identified family members of the MMPs. All the family members share the signalling peptide, propeptide, catalytic and hemopexin-like domains. MMP-2 and MMP-9 also share a fibronectin linker (Reproduced from reference 2). CMMP MMPs from chicken embryo fibroblasts; MT Membrane-type; XMMP MMPs from the frog Xenopus laevis embryos

Figure 2)

Mechanisms of regulation of matrix metalloproteinases (MMPs). The presence of proenzyme is regulated through transcriptional activation by inflammatory cytokines. The proenzyme can be converted into an activated enzyme by a number of environmental influences. Finally, there are both natural and artificial inhibitors to modulate their potent biological action by providing a variety of checks and balances. ACE Angiotensin-converting enzyme; EMMPRIN Extracellular MMP inducers; IL Interleukin; MT Membrane-type; OFR Oxygen free radicals; TIMP Tissue inhibitors of metalloproteinases; TNF Tumour necrosis factor; uPA Urokinase-type plasminogen activator; Zn Zinc

Figure 3)

Actively remodelling atherosclerotic plaque that can lead to plaque rupture. In a remodelling plaque, there is a balance between matrix synthesis and matrix degradation – the latter is mediated by matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-3. The MMP activation and, hence, matrix degradation is enhanced by the presence of cytokines such as tumour necrosis factor (TNF), interferons (IFNs) elaborated by macrophages, T lymphocytes and activated smooth muscle cells (SMCs). This is stimulated by the presence of oxidized low density lipoprotein (LDL) and C-reactive protein (CRP). In the presence of infection, inflammation or excessive mechanical stress, the MMP activity can further hasten the disintegration of the fibrous cap, leading to plaque rupture and its consequences

Figure 4)

Postinfarction ventricular rupture is partially dependent on the presence of tumour necrosis factor (TNF) activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the myocardium. In this mouse model (6), the wild-type (WT) animals suffer significant mortality from rupture postinfarction due to very high levels of MMP-9. However, in the TNF knockout animals, in whom the cytokine levels were much lower, there was a reduction in MMP-9 and a minimal amount of rupture. B Infarct border; Is Infarct region; N Noninfarct region; S Sham

Figure 5)

In a model of viral myocarditis, the affected cardiac tissue often undergoes remodelling and necrosis, with a significant amount of inflammatory infiltration (Left) (12). However, in the same model, when exposed to an elastase inhibitor, not only were the tissue necrosis and remodelling attenuated, but there was also a surprising degree of reduction of inflammatory cell infiltration (Right). This suggests that there is a vicious cycle set up in which inflammation begets matrix metalloproteinase activation, which begets more inflammation