Matrix Metalloproteinase-2 Expression by Vascular Smooth Muscle Cells Is Mediated by Both Stimulatory and Inhibitory Signals in Response to Growth Factors

Risinger, George M.; Hunt, Tamara S.; Updike, Dawn L.; Bullen, Elizabeth C.; Howard, Eric W.

doi:10.1074/jbc.m513513200

Cited by 68 publications

(75 citation statements)

References 61 publications

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“…To investigate pathways through which insulin and FFAs may have affected MMPs, we examined key terminal targets of several insulin signaling cascades. Previous reports have implicated insulin or IGF-1 signaling through the PI3K/Akt cascade as being responsible for stimulation of MMP activity (18,24). In vascular tissues, this pathway controls the metabolic actions of insulin (including glucose and amino acid uptake, glycogen synthesis, and nitric oxide production) (25) and is inhibited by FFA in major insulin target tissues (14).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta

et al. 2008

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OBJECTIVE-Obesity is associated with insulin resistance, hyperinsulinemia, elevated plasma free fatty acid (FFA), and increased risk for atherosclerotic vascular disease (ASVD). A part of this increased risk may be due to enhanced activation of matrix metalloproteinases (MMPs). Here, we have examined the effects of physiologically elevated levels of insulin and FFA on three MMPs and their inhibitors (tissue inhibitors of MMP [TIMPs]) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping.RESEARCH DESIGN AND METHODS-Four-hour euglycemic-hyperinsulinemic clamps with infusion of saline/glycerol, lipid/heparin, or insulin with or without lipid/heparin were performed in alert unrestrained male rats.RESULTS-Hyperinsulinemia increased MMP-2 (ϳ6-fold), MMP-9 (ϳ13-fold), membrane type 1-MMP (MT1-MMP; ϳ8-fold) (all Western blots), and gelatinolytic activity (zymography) of MMP-2 (2-fold), while not affecting TIMP-1 and TIMP-2. Insulin increased IRS-1-associated PI 3-kinase (PI3K), extracellular signal-regulated kinases 1/2 (ERK1/2), and c-jun NH 2 -terminal kinase (JNK) (by Western blots with phospho-specific antibodies). FFA augmented the insulin-mediated increases in MMP-2 (from ϳ6-to ϳ11-fold), MMP-9 (from ϳ3-to ϳ23-fold), MT1-MMP (from ϳ8-to ϳ20-fold), MMP-2 gelatinolytic activity (from 2-to 3-fold), and JNK and p38 mitogen-activated protein kinase (MAPK) activities but decreased insulin-mediated activation of PI3K and ERK1/2. Raising FFA without raising insulin affected neither MMPs nor TIMPs.CONCLUSIONS-FFA augmented insulin stimulation of the MMP/TIMP balance of three proatherogenic MMPs and increased activities of two MAPKs (JNK and p38 MAPK), both of which are known to stimulate the production of proinflammatory cytokines. This may, over time, increase degradation of extracellular matrix and together with inflammatory changes promote development of ASVD. Diabetes 57:476-483, 2008 M any obese people are insulin resistant (1,2). Insulin resistance, on the other hand, is one of the most important risk factors for the development and progression of atherosclerotic vascular disease (ASVD) (3,4). The relationship between insulin resistance and ASVD, however, is complex. On one hand, insulin resistance is associated with several established risk factors for ASVD such as type 2 diabetes, hypertension, atherogenic dyslipidemia, and abnormalities of blood coagulation and fibrinolysis (5). On the other hand, these associations cannot completely explain the obesity/insulin resistance-related ASVD risk, suggesting that there may be other, as yet unidentified, ways in which insulin resistance increases this risk (6). Indeed, there are reasons to believe that insulin resistance may increase ASVD by promoting matrix metalloproteinase (MMP) activity. MMPs are enzymes with proteolytic activity against connective tissue proteins such as collagen, proteoglycans, and elastin and there is accumulating evidence suggesting that they play a key role in the development of atherosclerotic lesions (rev. in 7). For instanc...

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Section: Discussionmentioning

confidence: 99%

In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta

et al. 2008

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“…A proteolytic cleavage by MMPs might activate these growth factors, which leads to HNSCC cell growth. TGF-β and IGF are factors known to increase the membrane MMP-2 expression in smooth muscle (51). HGF might enhance the invasiveness of HNSCC by the induction of Ets-related E1AF transcription factor genes, whose products again activate MMP genes (52).…”

Section: Discussionmentioning

confidence: 99%

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

et al. 2012

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Abstract. Head and neck squamous cell carcinoma (HNSCC)is an aggressive epithelial malignancy. It is known to be the most common neoplasm appearing in the upper aerodigestive tract. The poor 5-year survival rate has remained unchanged in the last decades even though improved techniques in surgery, radiation and chemotherapy have been established. In contrast to the overall decreasing incidence of head and neck cancer in the US, the incidence of HPV-associated oropharyngeal cancer is increasing, indicating the importance of viral etiology. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). Matrix metalloproteinases (MMP) have been shown to play key roles in the remodeling of the ECM. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. But it also has an inhibitory impact, e.g., on the protein-tyrosine-kinase (PTK) receptor c-kit and on its PTK activity in HNSCC. In this study, we incubated the HNSCC cell lines HNSCC 11A and 14C and the p16-positive SCC line CERV196 with increasing concentrations of imatinib or carboplatin. After an incubation time of up to 10 days, we evaluated MMP-2 and -14 expression by ELISA techniques and immunohistochemistry. MMP-2 and -14 expression was demonstrated in all incubated tumor cell lines. Especially incubation with imatinib resulted in a significant decrease in MMP expression in incubated cell lines. Our results indicate that the expression of MMP-2 and -14 is suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially keeping in mind the moderate toxicity of imatinib.

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“…A proteolytic cleavage by MMPs might activate these growth factors, which leads to HNSCC cell growth. TGF-ß and IGF are factors known to increase the membrane MT1-MMP expression in vascular smooth muscle (35). HGF might enhance the invasiveness of HNSCC by the induction of Ets-related E1AF transcription factor genes, whose products again activate MMP genes (36).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

Sauter¹

2011

Oncol Rep

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Abstract. Squamous cell carcinoma of the head and neck (HNSCC) is the most common neoplasm arising in the upper aerodigestive tract. Unfortunately, the survival for this type of cancer has not improved significantly in the past 25 years. To enhance the survival rate multimodal therapy regimens have been set up. In these regimens chemotherapy plays a pivotal role in the majority of advanced cases. Transmembrane proteintyrosine kinases (PTK) are fundamental elements of the signal transduction. In consequence, they might be promising targets for cancer therapy. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukemia. But imatinib also has an inhibitory impact on the PTK receptor c-kit and on its PTK activity. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). The ECM is altered by matrix metalloproteinases (MMP). In this study, we incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin. After an incubation time of up to 10 days, we evaluated c-kit, MMP-2 and MMP-14 by ELISA techniques and immunohistochemical methods. Especially the combination of 7.5 μmol carboplatin with 30 μmol imatinib resulted in a significant decrease in MMP-2 expression in all observed cell lines (p<0.05). We did not demonstrate a significant alteration in c-kit expression by imatinib and carboplatin. We observed an increase in apoptosis in HNSCC cells by the combination of the two observed chemotherapeutic drugs. In all cell lines tested, expression of c-kit and MMP could be demonstrated. Our results indicate that MMP-2 expression was suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially one keeping in mind the moderate toxicity of imatinib.

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Matrix Metalloproteinase-2 Expression by Vascular Smooth Muscle Cells Is Mediated by Both Stimulatory and Inhibitory Signals in Response to Growth Factors

Cited by 68 publications

References 61 publications

In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta

In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

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