Protease-Activated Receptor-1 Antagonist F 16618 Reduces Arterial Restenosis by Down-Regulation of Tumor Necrosis Factor α and Matrix Metalloproteinase 7 Expression, Migration, and Proliferation of Vascular Smooth Muscle Cells

Chieng-Yane, Pauline; Bocquet, Arnaud; Létienne, Robert; Bourbon, Thierry; Sablayrolles, Sylvie; Perez, Michel; Hatem, Stéphane N.; Lompré, Anne‐Marie; Grand, Bruno Le; David‐Dufilho, Monique

doi:10.1124/jpet.110.175182

Cited by 46 publications

(32 citation statements)

References 36 publications

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“…Although the direct relationship between MMP-1 and PAR1 in the atherosclerotic plaque has not yet been shown, genetic deletion of PAR1 or inhibition regulates neointimal hyperplasia after vessel damage in animal models. [70][71][72] Furthermore, as tissue factor may also be increased in atherosclerotic lesions, the contributions of thrombin-PAR1 versus MMP-PAR1 signaling in this context have not been examined. Future studies should be aimed at determining the functional agonist in these settings and whether direct inhibition of the protease would have any beneficial effect.…”

Section: Mmp1-par1 In Platelet Activation and Atherothrombosismentioning

confidence: 99%

Matrix metalloproteases and PAR1 activation

Austin

Covic

Kuliopulos

2013

Blood

164

151

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IntroductionProtease-activated receptors (PARs) are members of the G-protein coupled receptor superfamily whose cellular responses are driven through various G-protein and non-G-protein pathways, resulting in a diverse array of physiologic outputs. 1 PARs were identified Ͼ 20 years ago with the discovery of the first thrombin receptor, 2,3 later renamed PAR1. Elucidation of the unusual proteolytic mechanism of receptor activation paved the way for the subsequent discovery of PAR2, PAR3, and PAR4. 4 After the observation that human platelets could be activated by proteolytic cleavage of PAR1 by thrombin, many other members of the serine protease family were found to be capable of activating one or another of the PARs, including plasmin, activated protein C, thrombocytin, PA-BJ, factor Xa, factor VIIa, kallikreins, cathepsin G, trypsin, matriptase, and tryptase. [5][6][7][8] Considering that PARs were initially identified as thrombin receptors, their role in the vasculature is paramount. 1 PARs are expressed on nearly all cell types in the blood vessel wall and blood, the notable exception being red blood cells. 1 PAR1 is the high-affinity thrombin receptor and is expressed on the surface of endothelium, smooth muscle cells, platelets, neutrophils, macrophages, and leukemic white cells. 9,10 Thrombin activation of PAR1 promotes platelet aggregation, shape change, adhesion, cell proliferation, chemokine production, and migration via G q , G i , and G 12/13 pathways. 11 In this review, we focus on the unexpected discovery that the zinc-dependent matrix metalloprotease-1 (MMP-1) is able to cleave and activate PAR1 at a noncanonical site, 12 which leads to a signaling pattern in platelets and other cells distinct from that seen with thrombin. Platelets harbor abundant proMMP-1 zymogen on their surface, 13 which is converted to active MMP-1 after exposure to collagen fibrils. 12 Recently, a second MMP, MMP-13, was identified as having the capacity to cleave and activate PAR1 on cardiac fibroblasts and cardiomyocytes, resulting in pathologic activation of downstream signaling events that contribute to heart failure. 14 Emerging evidence suggests that selective proteolytic activation of PAR1 by MMPs, such as MMP-1 and MMP-13, will be important contributors to the evolution of a variety of disease processes, including thrombus initiation and thrombosis, atherosclerosis and restenosis, sepsis, angiogenesis, heart failure, and cancer ( Figure 1). Divergence in the MMP familyMMPs compose a family of 28 zinc-dependent endopeptidases, which are further subdivided based on their distinct, albeit overlapping, substrate specificity. 15 MMP-1, -8, and -13, otherwise known as the interstitial collagenases, are capable of initiating the degradation of fibrillar-type collagens by cleaving at a single site threefourths of the way from the N-terminus. 16 Because collagen is the most abundant protein in the human body, the collagenases represent an essential enzyme class involved in normal development and tissue repair. 17 MMP-2 and -...

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Section: Mmp1-par1 In Platelet Activation and Atherothrombosismentioning

confidence: 99%

Matrix metalloproteases and PAR1 activation

Austin

Covic

Kuliopulos

2013

Blood

164

151

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“…Human UCB-MSCs were seeded at 4 · 10 4 cells on low 35-mm dishes with both silicone reservoirs, which are separated by a 500-mm thick wall (Ibidi, Martinsried, Germany) [21] and incubated until the cell reached around 100% confluence in serum-containing medium. After serum starvation for 24 h, the silicone reservoirs were removed with sterile forceps to create a wound field.…”

Section: Wound-healing Migration Assaymentioning

confidence: 99%

Netrin-1 Induces MMP-12-Dependent E-Cadherin Degradation Via the Distinct Activation of PKCα and FAK/Fyn in Promoting Mesenchymal Stem Cell Motility

Lee

Jung

et al. 2014

Stem Cells and Development

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Netrin-1 (Ntn-1) is a potent inducer of neuronal cell migration; however, its molecular mechanism that guides the migratory behavior of stem cells has not been characterized. In this study, we investigate the role of Ntn-1 in promoting the motility of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and its related signaling pathways. Ntn-1 (50 ng/mL) significantly increased motility of UCB-MSCs, which was inhibited by blocking antibodies for deleted in colorectal cancer (DCC) and integrin (IN) a6b4. Ntn-1 in DCC stimulated protein kinase Ca (PKCa) activation, but not PKCe, PKCy, and PKCz, while Ntn-1 in INa6b4 induced the phosphorylation of focal adhesion kinase (FAK) and Fyn. Notably, Ntn-1 induced phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases ( JNK), and nuclear factor kappa-B (NF-kB), but they were concurrently downregulated by blocking the activities of PKCa, FAK, and Fyn. Ntn-1 uniquely increased the MMP-12 expression of all the matrix metalloproteinase (MMP) isoforms present in UCB-MSCs, though this was significantly blocked by an NF-kB inhibitor. Finally, Ntn-1 induced the MMP-12-dependent degradation of E-cadherin (E-cad), while Ntn-1 abrogated the interaction between E-cad and p120-catenin. In addition, Ntn-1 has the ability to stimulate cytoskeletal reorganization-related proteins, such as Cdc42, Rac1, Profilin-1, Cofilin-1, a-Actinin-4, and filamentous actin (F-actin) in UCB-MSCs. These results demonstrate that Ntn-1 induces MMP-12-dependent E-cad degradation via the distinct activation of PKCa and FAK/Fyn, which is necessary to govern the activation of ERK, JNK, and NF-kB in promoting motility of UCBMSCs.

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“…Human UCB-MSCs were seeded at 4 × 10 4 cells in both silicone reservoirs, which were separated by a 500 μm thick wall (Ibidi, Martinsried, Germany) (Chieng-Yane et al, 2011) and incubated until the cell reached around 100% confluence in the serum-containing medium. After incubation in serumfree medium (serum starvation) for 24 h, the silicone reservoirs were removed with sterile forceps to create a wound field.…”

Section: In Vitro Wound-healing Assaymentioning

confidence: 99%

Reactive oxygen species induce MMP12‐dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord‐derived mesenchymal stem cells

Yun

Lee

et al. 2014

British J Pharmacology

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Background and PurposeReactive oxygen species (ROS) are potent regulators of stem cell behaviour; however, their physiological significance as regards MMP‐mediated regulation of the motility of human umbilical cord blood‐derived mesenchymal stem cells (UCB‐MSCs) has not been characterized. In the present study, we investigated the role of hydrogen peroxide (H2O2) and associated signalling pathways in promoting UCB‐MSCs motility.Experimental ApproachThe regulatory effects of H2O2 on the activation of PKC, MAPKs, NF‐κB and β‐catenin were determined. The expressions of MMP and extracellular matrix proteins were examined. Pharmacological inhibitors and gene‐specific siRNA were used to identify the signalling pathways of H2O2 that affect UCB‐MSCs motility. An experimental skin wound‐healing model was used to confirm the functional role of UCB‐MSCs treated with H2O2 in ICR mice.Key ResultsH2O2 increased the motility of UCB‐MSCs by activating PKCα via a calcium influx mechanism. H2O2 activated ERK and p38 MAPK, which are responsible for the distinct activation of transcription factors NF‐κB and β‐catenin. UCB‐MSCs expressed eight MMP genes, but only MMP12 expression was uniquely regulated by NF‐κB and β‐catenin activation. H2O2 increased the MMP12‐dependent degradation of collagen 5 (COL‐5) and fibronectin (FN) associated with UCB‐MSCs motility. Finally, topical transplantation of UCB‐MSCs treated with H2O2 enhanced skin wound healing in mice.Conclusions and ImplicationsH2O2 stimulated UCB‐MSCs motility by increasing MMP12‐dependent degradation of COL‐5 and FN through the activation of NF‐κB and glycogen synthase kinase‐3β/β‐catenin, which is critical for providing a suitable microenvironment for MSCs transplantation and re‐epithelialization of skin wounds in mice.

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Protease-Activated Receptor-1 Antagonist F 16618 Reduces Arterial Restenosis by Down-Regulation of Tumor Necrosis Factor α and Matrix Metalloproteinase 7 Expression, Migration, and Proliferation of Vascular Smooth Muscle Cells

Cited by 46 publications

References 36 publications

Matrix metalloproteases and PAR1 activation

Matrix metalloproteases and PAR1 activation

Netrin-1 Induces MMP-12-Dependent E-Cadherin Degradation Via the Distinct Activation of PKCα and FAK/Fyn in Promoting Mesenchymal Stem Cell Motility

Reactive oxygen species induce MMP12‐dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord‐derived mesenchymal stem cells

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