Matrix Metalloproteinases and their Tissue Inhibitors in Diabetes, Atherosclerosis and Prediction of the Cardiovascular Risk

Viola      Vargova; Marek      Pytliak; Viola      Mechirova

Abstract

The interaction between cells and extracellular matrix plays a key role in normal development and differentiation of the organism. Changes in extracellular matrix are regulated by the system of proteolytic enzymes that are responsible for proteolysis of many components of extracellular matrix. By regulating the composition and integrity of the extracellular matrix, this group of enzymes is essential for inducing processes of cell proliferation, differentiation and apoptosis. Matrix metalloproteinases (MMPs) represent the main group of regulatory proteases in ECM. Their activity is regulated at multiple levels, including regulation of transcription, secretion, activation and inhibition. In particular, inhibition of MMP is carried out with the tissue inhibitors of metalloproteinase family - TIMPs. However, there is only a little knowledge about the prognostic impact of the TIMPs/matrix metalloproteinase complex in patients with future cardiovascular events or cardiovascular death. Atherosclerotic plaque formation occurs as a result of cellular migration and proliferation accompanied by an accumulation of ECM. MMP-2-dependent vascular degradation of extracellular matrix promotes smooth muscle cells migration and early plaque development. Immunocytochemistry, zymography and in situ hybridization studies have demonstrated an increased expression of different MMPs in human atherosclerotic plaques. Recent works have shown an increase of MMP-9 in unstable carotid plaques. Furthermore, a significant increase in circulating MMP-9 levels was observed in patients after myocardial infarction, patients undergoing carotid endarterectomy with evidence of ongoing spontaneous embolization and other cardiovascular events. MMP-8 has been implicated in atherosclerotic plaque destabilization through its capacity to thin the protecting fibrous cap, thus rendering it more vulnerable to rupture. Increased plaque MMP-8 activity has been observed in asymptomatic patients with plaque progression. Also, plaques prone to rupture express more immunoreactive MMP-8 compared with lesions with more stable morphology. On the other hand, TIMP-1 appears to play an important role in regulation of left ventricle structure and systolic function. Plasma TIMP-1 concentration is also increased in acute coronary syndrome and serum TIMP-1 is associated with the presence of carotid lesions as well. In the Framingham heart study, total TIMP-1 was related to major cardiovascular risk factors, in particular hypertension which may influence vascular and cardiac remodelling via extracellular matrix degradation. In the present article the authors offer an overview of possible mechanisms of action of MMPs and TIMPs and their predictive value in estimating the cardiovascular risk.

Keywords: Matrix metalloproteinases, TIMPs, cardiovascular risk, atherosclerosis, extracellular matrix plays, proteolytic enzymes, proteolysis, Atherosclerotic plaque, atherosclerotic plaque destabilization, carotid lesions