Crucial Role of Membrane Type 1 Matrix Metalloproteinase (MT1- MMP) in RhoA/Rac1-Dependent Signaling Pathways in Thrombin- Stimulated Endothelial Cells

Ando, Kenichi; Ishibashi, Toshiyuki; Ohkawara, Hiroshi; Inoue, N.; Sugimoto, Koichi; Uekita, Hironori; Hu, Chengjun; Okamoto, Yasuo; Takuwa, Yoh; Takeishi, Yasuchika

doi:10.5551/jat.6783

Cited by 11 publications

(12 citation statements)

References 33 publications

(61 reference statements)

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“…MT1 -MMP is a signaling molecule of vascular proatherogenic changes induced by several proinflammatory and proatherogenic stimuli, which linked to impaired vascular cell function in the pathology of atherosclerosis and subsequent cardiovascular disease 32,47,60,73,80) .…”

Section: Discussionmentioning

confidence: 99%

“…3B). Our findings suggest that MT1 -MMP mediates thrombin -triggered RhoA and Rac1 activation and Ca 2+ signaling in ECs, suggesting that thrombin -triggered MT1 -MMP -related signaling may be a target for endothelial dysfunction and oxidant stress in the pathogenesis of cardiovascular diseases 60) .…”

Section: Roles Of Mt1 -Mmp In Rhoa/rac1 -Dependent Signaling Pathwaysmentioning

confidence: 99%

“…TNF -α induced the increased levels of TF antigen and activity and reduced the antigen levels of thrombomodulin (TM), which directly blocks the interaction between thrombin and the procoagulant protein substrates in the pathogenesis of vascular disease 69,70) . MT1 -MMP possesses transmembrane and cytoplasmic domains in addition to extracellular domains, and the cytoplasmic domain of MT1 -MMP has an important role in cell invasion and proliferation, indi- ] i increase and TF and PAI -1 expression in ECs, whereas Rac1 activation induced thrombin -triggered ROS generation and TF and PAI -1 expression 60) . B. MT1 -MMP mediates thrombintriggered RhoA and Rac1 activation, resulting in the downstream events including Ca 2+ signaling, NADPH oxidase activity, ROS generation, and TF and PAI -1 expression.…”

Section: Impact Of Mt1 -Mmp On Akt Phosphorylation In Tnf -α Stimulationmentioning

confidence: 99%

“…NADPH oxidase in AGE/ RAGE -mediated generation of ROS enhanced the expression levels of TF upon stimulation with AGE 83) . Rac1 activation -dependent ROS production induced thrombin -induced upregulation of TF, which is one of the redox -sensitive, signaling -dependent molecules 60) . Our findings suggest that HMGB -1 -stimulated Rac1 activation induces NADPH oxidase -mediated ROS generation and TF upregulation 80) (Fig.…”

Section: Sclerosis In Apoementioning

confidence: 99%

“…B. MT1 -MMP mediates thrombintriggered RhoA and Rac1 activation, resulting in the downstream events including Ca 2+ signaling, NADPH oxidase activity, ROS generation, and TF and PAI -1 expression. MT1 -MMP contributes to the RhoA/Ca 2+ and Rac1/NADPH oxidase -dependent signaling pathways in thrombin -induced vascular responses in ECs 60) .…”

Section: Impact Of Mt1 -Mmp On Akt Phosphorylation In Tnf -α Stimulationmentioning

confidence: 99%

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Membrane Type 1-Matrix Metalloproteinase (Mt1-Mmp) Identified as a Multifunctional Regulator of Vascular Responses

Ohkawara

Ikeda

Ogawa

et al. 2015

FJMS

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:Membrane type 1 -matrix metalloproteinase (MT1 -MMP) functions as a signaling molecules in addition to a transmembrane metalloprotease, which degrades interstitial collagens and extracellular matrix components. This review focuses on the multifunctional roles of MT1 -MMP as a signaling molecule in vascular responses to pro -atherosclerotic stimuli in the pathogenesis of cardiovascular diseases. First, the lectin -like oxidized low -density lipoprotein receptor -1 (LOX -1) -MT1 -MMP signaling axis contributes to endothelial dysfunction, which is mediated via small GTP -binding protein RhoA and Rac1 activation. Second, MT1 -MMP plays a crucial role in reactive oxygen species (ROS) generation through the activation of receptor for advanced glycation end products (AGEs) in smooth muscle cells, indicating that MT1 -MMP may be a therapeutic target for diabetic vascular complications. Third, MT1 -MMP is involved in RhoA/Rac1 activation and Ca 2+ signaling in the mechanism of thrombin -stimulated endothelial dysfunction and oxidant stress. Fourth, the inhibition of the MT1 -MMP/Akt signaling pathway may be an attractive strategy for treating endothelial disordered hemostasis in the development of vascular diseases linked to TNF -α -induced inflammation. Fifth, MT1 -MMP through RAGE induced RhoA/Rac1 activation and tissue factor protein upregulation through NF -κB phosphorylation in endothelial cells stimulated by high -mobility group box -1, which plays a key role in the systemic inflammation. These findings suggest that the MT1 -MMP -mediated signaling axis may be a promising target for treating atherosclerosis and subsequent cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Roles Of Mt1 -Mmp In Rhoa/rac1 -Dependent Signaling Pathwaysmentioning

confidence: 99%

Section: Impact Of Mt1 -Mmp On Akt Phosphorylation In Tnf -α Stimulationmentioning

confidence: 99%

Section: Sclerosis In Apoementioning

confidence: 99%

Section: Impact Of Mt1 -Mmp On Akt Phosphorylation In Tnf -α Stimulationmentioning

confidence: 99%

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Membrane Type 1-Matrix Metalloproteinase (Mt1-Mmp) Identified as a Multifunctional Regulator of Vascular Responses

Ohkawara

Ikeda

Ogawa

et al. 2015

FJMS

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Matrix metalloproteinase 14 modulates signal transduction and angiogenesis in the cornea

Chang

Huang

Cunningham

et al. 2016

Survey of Ophthalmology

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The cornea is transparent and avascular, and retention of these characteristics is critical to maintaining vision clarity. Under normal conditions, wound healing in response to corneal injury occurs without the formation of new blood vessels; however, neovascularization may be induced during corneal wound healing when the balance between proangiogenic and antiangiogenic mediators is disrupted to favor angiogenesis. Matrix metalloproteinases (MMPs), which are key factors in extracellular matrix remodeling and angiogenesis, contribute to the maintenance of this balance, and in pathologic instances, can contribute to its disruption. Here, we elaborate on the facilitative role of MMPs, specifically MMP-14, in corneal neovascularization. MMP-14 is a transmembrane MMP that is critically involved in extracellular matrix proteolysis, exosome transport, and cellular migration and invasion, processes that are critical for angiogenesis. To aid in developing efficacious therapies that promote healing without neovascularization, it is important to understand and further investigate the complex pathways related to MMP-14 signaling, which can also involve vascular endothelial growth factor, basic fibroblast growth factor, Wnt/β-catenin, transforming growth factor, platelet-derived growth factor, hepatocyte growth factor or chemokines, epidermal growth factor, prostaglandin E2, thrombin, integrins, Notch, Toll-like receptors, PI3k/Akt, Src, RhoA/RhoA kinase, and extracellular signal-related kinase. The involvement and potential contribution of these signaling molecules or proteins in neovascularization are the focus of the present review.

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Polymorphisms in the RAC1 Gene Are Associated With Hypertension Risk Factors in a Chilean Pediatric Population

Tapia-Castillo

Carvajal

Campino

et al. 2014

American Journal of Hypertension

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Crucial Role of Membrane Type 1 Matrix Metalloproteinase (MT1- MMP) in RhoA/Rac1-Dependent Signaling Pathways in Thrombin- Stimulated Endothelial Cells

Cited by 11 publications

References 33 publications

Membrane Type 1-Matrix Metalloproteinase (Mt1-Mmp) Identified as a Multifunctional Regulator of Vascular Responses

Membrane Type 1-Matrix Metalloproteinase (Mt1-Mmp) Identified as a Multifunctional Regulator of Vascular Responses

Matrix metalloproteinase 14 modulates signal transduction and angiogenesis in the cornea

Polymorphisms in the RAC1 Gene Are Associated With Hypertension Risk Factors in a Chilean Pediatric Population

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