Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation

2014 ◽  
Vol 111 (06) ◽  
pp. 1089-1101 ◽  
Author(s):  
Massimo Lenti ◽  
Emanuela Falcinelli ◽  
Marcella Pompili ◽  
Paola De Rango ◽  
Valentina Conti ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Matrix Metalloproteinase ◽  
Platelet Activation ◽  
Matrix Metalloproteinase 2 ◽  
Atherosclerotic Plaques ◽  
Active Matrix ◽  
Carotid Plaques ◽  
Cerebrovascular Events ◽  
Human Carotid

SummaryPurified active matrix metalloproteinase-2 (MMP-2) is able to promote platelet aggregation. We aimed to assess the role of MMP-2 expressed in atherosclerotic plaques in the platelet-activating potential of human carotid plaques and its correlation with ischaemic events. Carotid plaques from 81 patients undergoing endarterectomy were tested for pro-MMP-2 and TIMP-2 content by zymography and ELISA. Plaque extracts were incubated with gel-filtered platelets from healthy volunteers for 2 minutes before the addition of a subthreshold concentration of thrombin receptor activating peptide-6 (TRAP-6) and aggregation was assessed. Moreover, platelet deposition on plaque extracts immobilised on plastic coverslips under high shear-rate flow conditions was measured. Forty-three plaque extracts (53%) potentiated platelet aggregation (+233 ± 26.8%), an effect prevented by three different specific MMP-2 inhibitors (inhibitor II, TIMP-2, moAb anti-MMP-2). The pro-MMP-2/TIMP-2 ratio of plaques potentiating platelet aggregation was significantly higher than that of plaques not potentiating it (3.67 ± 1.21 vs 1.01 ± 0.43, p<0.05). Moreover, the platelet aggregation-potentiating effect, the active-MMP-2 content and the active MMP-2/pro-MMP-2 ratio of plaque extracts were significantly higher in plaques from patients who developed a subsequent major cardiovascular event. In conclusion, atherosclerotic plaques exert a prothrombotic effect by potentiating platelet activation due to their content of MMP-2; an elevated MMP-2 activity in plaques is associated with a higher rate of subsequent ischaemic cerebrovascular events.

Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin

2014 ◽  
Vol 111 (01) ◽  
pp. 140-153 ◽  
Author(s):  
Christopher Mason ◽  
Stephen Lynch ◽  
James Benjamin ◽  
Dani Ashak ◽  
Jamunabai M. Prakash ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Matrix Metalloproteinase ◽  
Platelet Activation ◽  
Matrix Metalloproteinase 2 ◽  
Activation Pathway ◽  
Extracellular Signals ◽  
Mmp Inhibitor ◽  
Activation Mechanisms ◽  
Vitro Analysis

SummaryMatrix metalloproteinase (MMP) activity is generally associated with normal or pathological extracellular processes such as tissue remodeling in growth and development or in tumor metastasis and angiogenesis. Platelets contain at least three MMPs, 1, 2 and 9 that have been reported to stimulate or inhibit agonist-induced platelet aggregation via extracellular signals. The non-selective Zn+2 chelating MMP inhibitor, 1,10-phenanthroline, and the serine protease inhibitor, AEBSF, were found to inhibit all tested agonist-induced platelet aggregation reactions. In vitro analysis demonstrated that 1,10-phenanthroline completely inhibited MMP-1,2,and 9 but had little to no effect on calpain activity while the converse was true with AEBSF. We now demonstrate that MMP-2 functions intracellularly to regulate agonistinduced platelet aggregations via the hydrolytic activation of talin, the presumed final activating factor of glycoprotein (GP)IIb/IIIa integrin (the inside-out signal). Once activated GPIIb/IIIa binds the dimeric fibrinogen molecule required for platelet aggregation. The active intracellular MMP-2 molecule is complexed with JAK 2/STAT 3, as demonstrated by the fact that all three proteins are co-immunoprecipitated with either anti-JAK 2, or anti-STAT 3 antibodies and by immunofluorescence studies. The MMP-2 platelet activation pathway can be synergistically inhibited with the non-selective MMP inhibitor, 1,10-phenanthroline, plus a JAK 2 inhibitor. This activation pathway is distinct from the previously reported calpain-talin activating pathway. The identification of a new central pathway for platelet aggregation presents new potential targets for drug regulation and furthers our understanding of the complexity of platelet activation mechanisms.

scholarly journals The Role of Matrix Metalloproteinase-9 in Atherosclerotic Plaque Instability

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Tiewei Li ◽  
Xiaojuan Li ◽  
Yichuan Feng ◽  
Geng Dong ◽  
Yuewu Wang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Atherosclerotic Plaque ◽  
Predictive Biomarker ◽  
Matrix Metalloproteinase 9 ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Cerebrovascular Events ◽  
Plaque Inflammation ◽  
Metalloproteinase 9

Matrix metalloproteinase-9 (MMP-9) belongs to the MMP family and has been widely investigated. Excessive MMP-9 expression can enhance extracellular matrix degradation and promote plaque instability. Studies have demonstrated that MMP-9 levels are higher in vulnerable plaques than in stable plaques. Additionally, several human studies have demonstrated that MMP-9 may be a predictor of atherosclerotic plaque instability and a risk factor for future adverse cardiovascular and cerebrovascular events. MMP-9 deficiency or blocking MMP-9 expression can inhibit plaque inflammation and prevent atherosclerotic plaque instability. All of these results suggest that MMP-9 may be a useful predictive biomarker for vulnerable atherosclerotic plaques, as well as a therapeutic target for preventing atherosclerotic plaque instability. In this review, we describe the structure, function, and regulation of MMP-9. We also discuss the role of MMP-9 in predicting and preventing atherosclerotic plaque instability.

On The Mechanism Of Heparin-Induced Potentiation Of Platelet Aggregation

1981 ◽  
Author(s):  
M Yamamoto ◽  
K Watanabe ◽  
Y Ando ◽  
H Iri ◽  
N Fujiyama ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Coagulation Factors ◽  
Marked Enhancement ◽  
Matrix Bound ◽  
Induced Aggregation ◽  
Aggregation Of Platelets ◽  
Plasma Heparin

It has been suggested that heparin caused potentiation of aggregation induced by ADP or epinephrine. The exact mechanism of heparin-induced platelet activation, however, remained unknown. In this paper, we have investigated the role of anti-thrombin III ( AT ) in heparin-induced platelet activation using purified AT and AT depleted plasma. When ADP or epinephrine was added to citrated PRP one minute after addition of heparin ( 1 u/ml, porcine intestinal mucosal heparin, Sigma Co. USA ), marked enhancement of platelet aggregation was observed, compared with the degree of aggregation in the absence of heparin. However, in platelet suspensions prepared in modified Tyrode’s solution, heparin exhibited no potentiating effect on platelet aggregation induced by epinephrine or ADP. Potentiation of epinephrine- or ADP-induced platelet aggregation by heparin was demonstrated when purified AT was added to platelet suspensions at a concentration of 20 μg/ml. AT depleted plasma, which was prepared by immunosorption using matrix-bound antibodies to AT, retained no AT, while determination of α1-antitrypsinα2- macroglobulin and fibrinogen in AT depleted plasma produced values which corresponded to those of the original plasma when dilution factor was taken into account. The activities of coagulation factors were also comparable to those of the original plasma. Heparin exhibited potentiating effect on ADP- or epinephrine-induced aggregation of platelets in original plasma, but no effect in AT depleted plasma. When purified AT was added back to AT depleted plasma at a concentration of 20 μg/ml, potentiation of platelet aggregation by heparin was clearly demonstrated.Our results suggest that effect of heparin on platelet aggregation is also mediated by anti-thrombin III.

Type I collagen from sea cucumber (Stichopus japonicus) and the role of matrix metalloproteinase-2 in autolysis

2021 ◽  
Vol 41 ◽  
pp. 100959
Author(s):  
Long-Jie Yan ◽  
Le-Chang Sun ◽  
Kai-Yuan Cao ◽  
Yu-Lei Chen ◽  
Ling-Jing Zhang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Sea Cucumber ◽  
Type I Collagen ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Stichopus Japonicus

Active matrix metalloproteinase-2 promotes apoptosis of hepatic stellate cells via the cleavage of cellular N-cadherin

2009 ◽  
Vol 29 (7) ◽  
pp. 966-978 ◽  
Author(s):  
Stephen N. Hartland ◽  
Frank Murphy ◽  
Rebecca L. Aucott ◽  
Armand Abergel ◽  
Xiaoying Zhou ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Matrix Metalloproteinase 2 ◽  
Active Matrix

scholarly journals Piezo1 mediates angiogenesis through activation of MT1-MMP signaling

2019 ◽  
Vol 316 (1) ◽  
pp. C92-C103 ◽  
Author(s):  
Hojin Kang ◽  
Zhigang Hong ◽  
Ming Zhong ◽  
Jennifer Klomp ◽  
Kayla J. Bayless ◽  
...  
Keyword(s):  
Shear Stress ◽  
Wall Shear Stress ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Sprouting Angiogenesis ◽  
Sphingosine 1 Phosphate ◽  
Wall Shear ◽  
Membrane Type

Angiogenesis is initiated in response to a variety of external cues, including mechanical and biochemical stimuli; however, the underlying signaling mechanisms remain unclear. Here, we investigated the proangiogenic role of the endothelial mechanosensor Piezo1. Genetic deletion and pharmacological inhibition of Piezo1 reduced endothelial sprouting and lumen formation induced by wall shear stress and proangiogenic mediator sphingosine 1-phosphate, whereas Piezo1 activation by selective Piezo1 activator Yoda1 enhanced sprouting angiogenesis. Similarly to wall shear stress, sphingosine 1-phosphate functioned by activating the Ca2+ gating function of Piezo1, which in turn signaled the activation of the matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase during sprouting angiogenesis. Studies in mice in which Piezo1 was conditionally deleted in endothelial cells demonstrated the requisite role of sphingosine 1-phosphate-dependent activation of Piezo1 in mediating angiogenesis in vivo. These results taken together suggest that both mechanical and biochemical stimuli trigger Piezo1-mediated Ca2+ influx and thereby activate matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase and synergistically facilitate sprouting angiogenesis.

Sign in / Sign up

Export Citation Format

Share Document