Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway

Moshal, Karni S.; Sen, Utpal; Tyagi, Neetu; Henderson, Brooke C.; Steed, Mesia; Ovechkin, Alexander V.; Tyagi, Suresh C.

doi:10.1152/ajpcell.00359.2005

Cited by 89 publications

(82 citation statements)

References 39 publications

(35 reference statements)

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“…Thus, its ability to reverse Hcy effects confirms the already described ability of homocysteine to activate PKC [34] and is in agreement with recent observations in endothelial cells, where both staurosporine (a PKC inhibitor) and NAC reduced homocysteine-induced MMP9 activation [35].…”

Section: Discussionsupporting

confidence: 92%

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

et al. 2006

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Aims/hypothesis Atherosclerosis is particularly aggressive in patients with diabetes. Hyperhomocysteinaemia causes oxidative stress and cytokine secretion: its atherogenic effect is mediated by an enhanced inflammatory response. Matrix metalloproteinases (MMPs) regulate extracellular matrix degradation and remodelling, and contribute to the vulnerability of the atherosclerotic lesion. Fibroblasts contribute to collagen biosynthesis and participate in plaque remodelling via expression and release of MMP2 and MMP9. To explore the role of hyperhomocysteinaemia in cellular pathways involved in plaque growth and stability in diabetic patients, we studied the effect of hyperhomocysteinaemia in human fibroblasts grown in the presence of normal or high glucose concentrations. Materials and methods In fibroblasts of five normal subjects, grown at 5.5 or 22 mmol/l glucose and treated with homocysteine, we determined: (1) MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP)-1 (an MMP inhibitor) production by western blot analysis; (2) their activity by zymography; (3) TGFB1 expression by real-time PCR; and (4) TGFB, fibronectin and IL6 release by ELISA. Results Hyperhomocysteinaemia increased the production and enzymatic activity of MMP2 and MMP9, the effect being more pronounced in high glucose. Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose. Hyperhomocysteinaemia also stimulated IL6 release, at least in part through nuclear factor-κB activation. TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose. Conclusions/interpretation Homocysteine upregulates the MMP-TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose. These actions of homocysteine may contribute to the increased atherogenesis observed in diabetic patients with poor metabolic control.

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Section: Discussionsupporting

confidence: 92%

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

et al. 2006

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“…The elevated Erk activity may account for the increased survival of the KO MEFs. The KO MEFs were more sensitive to the general apoptosis inducer, staurosporine (12,13), indicating that these cells are selectively resistant to anoikis, not apoptosis in general. The target for Bit1 activity in the Erk regulation appears to be an Erk phosphatase.…”

Section: Discussionmentioning

confidence: 96%

Anoikis effector Bit1 negatively regulates Erk activity

Kairouz-Wahbe

Biliran

Luo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Bcl-2 inhibitor of transcription (Bit1) is a mitochondrial protein that functions as a peptidyl-tRNA hydrolase, but, when released into the cytoplasm, it elicits apoptosis. The proapoptotic function is uniquely counteracted by integrin-mediated cell attachment. We generated a conditional KO mouse of the Bit1 gene by using the Cre-LoxP recombination system. Bit1-null mice were born alive but with some developmental abnormalities. They developed a runting syndrome after birth and died within the first 2 weeks. Cultured fibroblasts from the Bit1-null embryos [mouse embryo fibroblasts (MEFs)] were more resistant to cell death induced by loss of attachment to extracellular matrix (anoikis) than cells from the wild-type or heterozygous littermates. MEFs and tissues from Bit1 KO mice displayed a marked increase in Erk phosphorylation. Knocking down Bit1 expression in cultured cells resulted in increased Erk activation, and partially knocking down Erk reversed the increased anoikis resistance of Bit1 knockdown. The enhanced Erk activation was associated with decreased Erk phosphatase activity. These studies establish the physiological significance of Bit1 activity and begin to delineate a Bit1 signaling pathway that acts through Erk regulation.apoptosis ͉ cell adhesion ͉ integrins ͉ kinases ͉ mitogen-activated

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“…Reports from other laboratories have demonstrated that in several cell types, including microvascular endothelial cells, MMP-9 synthesis is under the control of the ERK1/ERK2 pathway (30)(31)(32). Accordingly, we investigated to determine whether DA-induced inhibition of MMP-9 synthesis in CD45 -VEGFR2 + cells of the BM was through the ERK1/ERK2 pathway.…”

Section: Da Acted Through Its D 2 Receptors To Inhibit Mmp-9 Synthesimentioning

confidence: 95%

Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization

Chakroborty¹,

Chowdhury²,

Sarkar³

et al. 2008

J. Clin. Invest.

135

121

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Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway

Cited by 89 publications

References 39 publications

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

Anoikis effector Bit1 negatively regulates Erk activity

Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization

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