Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability

Abstract

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14hi TIMP-3lo rabbit foam cells are more invasive and more prone to apoptosis than MMP-14lo TIMP-3hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction.

Plasmatic biomarkers of inflammation correlate with 18FDG-PET-CT and microembolic signals in patients with carotid stenosis

“…MMPs are a class of proteases involved in extracellular matrix degradation, which appear to play a key role in the process of vascular remodeling during the course of vascular disease [34,35] . Numerous studies suggest that MMPs and in particular MMP-3, MMP-7, MMP-9 and MMP-12, may be involved in the process of plaque destabilization [36,37] . However there are conflicting results in particular regarding MMP-3.…”

MMP-14 and TGFβ-1 methylation in pituitary adenomas

“…Previous studies have reported that MMP-14 is associated with tuberculosis by regulating monocyte migration and collagen destruction (32), and with macrophage activation in atherosclerosis (33). TGF-β1 function has been observed in brain and nerve damage (34).…”

ANALYSIS OF DIFFERENTIAL ExPRESSION OF MATRIx METALLOPROTEASES IN STABLE AND UNSTABLE ATHEROSCLEROTIC LESIONS BY A METHOD OF FULL GENOME SEQUENCING OF RNA: PILOT STUDY

“…В результате инфильтрации покрышки атеросклеротической бляшки макрофа-гами и Т-лимфоцитами увеличивается продукция в ней воспалительных цитокинов, ингибирующих пролиферацию ГМК и синтез ими коллагена, а также индуцирующих апоптоз ГМК и протеоли-тическую активность макрофагов. В результате макрофаги и ГМК начинают секретировать проте-олитические MMP, разрушающие коллагены и эла-стин покрышки бляшки, что приводит к ее истон-чению/иссечению, изъязвлению, тромбозу и соот-ветствующим клиническим проявлениям острого коронарного синдрома [11,15].…”

“…Высокий уровень экс-прессии белка ММР-14 наблюдался в гладкомышеч-ных клетках и пенистых клетках атеросклеротиче-ской бляшки [2,11].…”