Matrix Gla Protein Abstracts 2

©

Identification of differentially expressed genes in human varicose veins: involvement of matrix gla protein in extracellular matrix remodeling.
            (Cario-Toumaniantz et al., 2007)  Download
This study was designed to identify the global pattern of differentially expressed genes in human varicose veins. Using suppressive subtractive hybridization, we identified overexpression of genes known to be associated with extracellular matrix remodeling, including collagen III, tissue inhibitor of metalloproteinases I, dermatopontin, matrix Gla protein (MGP) and tenascin C. Real-time polymerase chain reaction analysis confirmed the differential expression of these genes. The overexpression of MGP transcript was associated with increased MGP level in varicose veins, in particular the undercarboxylated form of the protein. Smooth muscle cells from varicose veins showed increased proliferation rate and enhanced matrix mineralization. This observation correlated with the presence of ectopic mineralization areas in the varicose vein walls. The use of warfarin, to inhibit MGP activity, or siRNA targeting MGP transcript induced a reduction in the exacerbated proliferation of varicose vein smooth muscle cells. Our results suggest that high expression of MGP in varicose veins may contribute to venous wall remodeling by affecting proliferation and mineralization processes probably through impaired carboxylation of MGP. In addition, suppressive subtractive hybridization results also produce a profile of differentially expressed genes in varicose veins, in particular extracellular matrix components. Further study of these genes will provide insights into their specific roles in the etiology of venous disease.

Prophylactic role of vitamin K supplementation on vascular inflammation in type 2 diabetes by regulating the NF-κB/Nrf2 pathway via activating Gla proteins.
            (Dihingia et al., 2018) Download
There is no previous study that has examined the relationship between circulating vitamin K1 (VK1) and vascular inflammation in type 2 diabetes (T2D). This study aims to examine the hypothesis that circulating VK1 deficiency may be associated with higher inflammation and insulin resistance in T2D patients and that VK1 supplementation regulates the NF-κB/Nrf2 pathway via activating VK-dependent Gla proteins and reduces vascular inflammation. The results showed that plasma VK1 levels were significantly lower and MCP-1, fasting glucose, HbA1c, and insulin resistance (HOMA-IR) were significantly higher in T2D patients compared to those in the controls. The lower levels of VK1 in T2D patients were significantly and inversely correlated with MCP-1 and HOMA-IR, which suggests that VK1 supplementation may reduce the vascular inflammation and insulin resistance in T2D. Using a high fat diet-fed T2D mice model this study further demonstrated that VK1 supplementation (1, 3, 5 μg per kg BW, 8 weeks) dose-dependently decreased the body weight gain, glucose intolerance, fasting glucose, glycated hemoglobin, HOMA-IR, and cytokine secretion (MCP-1 and IL-6) in T2D mice. Further cell culture studies showed that VK1 supplementation (1, 5, or 10 nM) decreased NF-κB phosphorylation and MCP-1 secretion and increased Nrf2 protein expression in high glucose (HG, 25 mM)-treated monocytes. Signal silencing studies with GGCX siRNA again depicted the role of VK-dependent Gla proteins in mediating the effect of VK1 on vascular inflammation in HG-treated cells. In conclusion, this study suggests that circulating VK1 has a positive effect in lowering vascular inflammation in T2D by regulating NF-κB/Nrf2 transcription factors via activating VK-dependent Gla proteins.

Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients.
            (Gheduzzi et al., 2007)  Download
Mature MGP (Matrix gamma-carboxyglutamic acid protein) is known to inhibit soft connective tissues calcification. We investigated its possible involvement in pseudoxanthoma elasticum (PXE), a genetic disorder whose clinical manifestations are due to mineralization of elastic fibers. PXE patients have lower serum concentration of total MGP compared to controls (P<0.001). Antibodies specific for the noncarboxylated (Glu-MGP) and for the gamma-carboxylated (Gla-MGP) forms of MGP were assayed on ultrathin sections of dermis from controls and PXE patients. Normal elastic fibers in controls and patients were slightly positive for both forms of MGP, whereas Gla-MGP was more abundant within control's than within patient's elastic fibers (P<0.001). In patients' calcified elastic fibers, Glu-MGP intensively colocalized with mineral precipitates, whereas Gla-MGP precisely localized at the mineralization front. Data suggest that MGP is present within elastic fibers and is associated with calcification of dermal elastic fibers in PXE. To investigate whether local cells produce MGP, dermal fibroblasts were cultured in vitro and MGP was assayed at mRNA and protein levels. In spite of very similar MGP mRNA expression, cells from PXE patients produced 30% less of Gla-MGP compared to controls. Data were confirmed by immunocytochemistry on ultrathin sections. Normal fibroblasts in vitro were positive for both forms of MGP. PXE fibroblasts were positive for Glu-MGP and only barely positive for Gla-MGP (P<0.001). In conclusion, MGP is involved in elastic fiber calcification in PXE. The lower ratio of Gla-MGP over Glu-MGP in pathological fibroblasts compared to controls suggests these cells may play an important role in the ectopic calcification in PXE.


 

Prognostic value of matrix Gla protein in breast cancer.
            (Yoshimura et al., 2009)  Download
To assess the prognostic value of matrix Gla protein (MGP) expression in cases of breast cancer, 9 samples from patients diagnosed with breast cancer who were followed up for more than 10 years were microdissected and then analyzed using Affymetrix U133 Plus 2.0 Arrays. Genes that exhibited significant differences in expression between patients with a good prognosis and those with a poor prognosis were identified. The MGP gene was among the genes up-regulated in cases where the prognosis was poor, indicating that the mRNA levels of MGP are a potential prognostic indicator of breast cancer. However, immunohistostaining of breast tissue microarrays (n=207) did not reveal a correlation between the protein expression of MGP and overall survival, neither was there a correlation between the protein expression of MGP and ER status or bone metastasis. In breast cancer cases, the mRNA level of MGP may be a marker indicating poor prognosis; however, protein expression determined by immunohistostaining is not.

 


References

Cario-Toumaniantz, C, et al. (2007), ‘Identification of differentially expressed genes in human varicose veins: involvement of matrix gla protein in extracellular matrix remodeling.’, J Vasc Res, 44 (6), 444-59. PubMed: 17643059
Dihingia, A, et al. (2018), ‘Prophylactic role of vitamin K supplementation on vascular inflammation in type 2 diabetes by regulating the NF-κB/Nrf2 pathway via activating Gla proteins.’, Food Funct, 9 (1), 450-62. PubMed: 29227493
Gheduzzi, D, et al. (2007), ‘Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients.’, Lab Invest, 87 (10), 998-1008. PubMed: 17724449
Yoshimura, K, et al. (2009), ‘Prognostic value of matrix Gla protein in breast cancer.’, Mol Med Rep, 2 (4), 549-53. PubMed: 21475864