scholarly journals Diabetic Vascular Calcification Mediated by the Collagen Receptor Discoidin Domain Receptor 1 via the Phosphoinositide 3-Kinase/Akt/Runt-Related Transcription Factor 2 Signaling Axis

2018 ◽  
Vol 38 (8) ◽  
pp. 1878-1889 ◽  
Author(s):  
Marsel Lino ◽  
Mark H. Wan ◽  
Antonio S. Rocca ◽  
David Ngai ◽  
Navid Shobeiri ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Vascular Calcification ◽  
Discoidin Domain Receptor ◽  
Signaling Axis ◽  
Related Transcription Factor ◽  
Phosphoinositide 3 Kinase ◽  
Collagen Receptor ◽  
Discoidin Domain Receptor 1

Abstract 677: The Role of Discoidin Domain Receptor 1 in Vascular Calcification in Atherosclerosis and Diabetes

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Marsel Lino ◽  
Michelle P Bendeck
Keyword(s):  
Signaling Pathway ◽  
Vascular Calcification ◽  
Kinase Domain ◽  
Plaque Burden ◽  
Tyrosine Kinase Domain ◽  
Discoidin Domain Receptor ◽  
Related Transcription Factor ◽  
Discoidin Domain Receptor 1

Background: Atherosclerosis and diabetes share many common pathogenic mechanisms. Vascular calcification is a common and severe complication in patients with atherosclerosis and type-2 diabetes (T2D), and occurs when vascular smooth muscle cells (VSMCs) trans-differentiate into osteoblast-like cells, in a process driven by runt-related transcription factor-2 (RUNX2). Our laboratory has recently discovered that Discoidin Domain Receptor-1 (DDR1) deletion reduces vascular calcification in vivo in Ldlr -/- mice. Additionally, we have shown that RUNX2 activity is reduced in Ddr1 -/- VSMCs. However, little is known about the mechanism by which DDR1 mediates calcification and RUNX2 activity. Rationale: The insulin signaling pathway plays an important role in T2D and VSMC function. It has recently been discovered that PI3K binds to the DDR1 tyrosine kinase domain upon DDR1 activation. Hypothesis: DDR1 promotes vascular calcification by inducing RUNX2 activity via the PI3K/Akt signaling pathway in T2D. Methods/Results: To study the role of DDR1 in vascular calcification in T2D, Ldlr -/- (SKO) and Ldlr-/-; Ddr1 -/- (DKO) mice were placed on a modified Western diet (40% fat, 43% carbohydrates, 0.5% cholesterol) for 12 weeks. Oil Red-O staining of the descending aorta showed reduced plaque burden in DKO mice (9.1±2.7% vs 4.4±2.9% surface area; p<0.05). Measurements of vascular calcification are ongoing. To determine the mechanism by which DDR1 modulates VSMC calcification, primary VSMCs collected from Ddr1 +/+ and DDR1 -/- mice were cultured in osteogenic media for 12 days to induce calcification. Proliferation and calcification were significantly reduced in DDR1 -/- VSMCs. Additionally, DDR1 -/- VSMCs showed significantly reduced p-Akt levels when stimulated with insulin. Significance: Current treatments for vascular calcification are non-specific and often pose a risk to bone health. This is the first study to test the role of DDR1 in vascular calcification in an animal model of T2D, which will provide novel insight into the mechanism of vascular calcification and uncover new potential therapeutic approaches.

scholarly journals Discoidin Domain Receptor 1 Protein Is a Novel Modulator of Megakaryocyte-Collagen Interactions

2013 ◽  
Vol 288 (23) ◽  
pp. 16738-16746 ◽  
Author(s):  
Vittorio Abbonante ◽  
Cristian Gruppi ◽  
Diana Rubel ◽  
Oliver Gross ◽  
Remigio Moratti ◽  
...  
Keyword(s):  
Type I Collagen ◽  
Type I ◽  
Discoidin Domain Receptor ◽  
Glycoprotein Vi ◽  
Protein Levels ◽  
Collagen Receptors ◽  
And Function ◽  
Extracellular Matrix Receptors ◽  
Collagen Receptor ◽  
Discoidin Domain Receptor 1

Growing evidence demonstrates that extracellular matrices regulate many aspects of megakaryocyte (MK) development; however, among the different extracellular matrix receptors, integrin α2β1 and glycoprotein VI are the only collagen receptors studied in platelets and MKs. In this study, we demonstrate the expression of the novel collagen receptor discoidin domain receptor 1 (DDR1) by human MKs at both mRNA and protein levels and provide evidence of DDR1 involvement in the regulation of MK motility on type I collagen through a mechanism based on the activity of SHP1 phosphatase and spleen tyrosine kinase (Syk). Specifically, we demonstrated that inhibition of DDR1 binding to type I collagen, preserving the engagement of the other collagen receptors, glycoprotein VI, α2β1, and LAIR-1, determines a decrease in MK migration due to the reduction in SHP1 phosphatase activity and consequent increase in the phosphorylation level of its main substrate Syk. Consistently, inhibition of Syk activity restored MK migration on type I collagen. In conclusion, we report the expression and function of a novel collagen receptor on human MKs, and we point out that an increasing level of complexity is necessary to better understand MK-collagen interactions in the bone marrow environment.

scholarly journals Inhibition of Collagen Receptor Discoidin Domain Receptor-1 (DDR1) Reduces Cell Survival, Homing, and Colonization in Lung Cancer Bone Metastasis

2012 ◽  
Vol 18 (4) ◽  
pp. 969-980 ◽  
Author(s):  
Karmele Valencia ◽  
Cristina Ormazábal ◽  
Carolina Zandueta ◽  
Diego Luis-Ravelo ◽  
Iker Antón ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Cell Survival ◽  
Discoidin Domain Receptor ◽  
Collagen Receptor ◽  
Discoidin Domain Receptor 1

scholarly journals The Interplay of WNT and PPARγ Signaling in Vascular Calcification

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2658
Author(s):  
Stefan Reinhold ◽  
W. Matthijs Blankesteijn ◽  
Sébastien Foulquier
Keyword(s):  
Transcription Factor ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Vascular Calcification ◽  
Atherosclerotic Plaque ◽  
Direct Interaction ◽  
Cardiovascular Death ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Related Transcription Factor

Vascular calcification (VC), the ectopic deposition of calcium phosphate crystals in the vessel wall, is one of the primary contributors to cardiovascular death. The pathology of VC is determined by vascular topography, pre-existing diseases, and our genetic heritage. VC evolves from inflammation, mediated by macrophages, and from the osteochondrogenic transition of vascular smooth muscle cells (VSMC) in the atherosclerotic plaque. This pathologic transition partly resembles endochondral ossification, involving the chronologically ordered activation of the β-catenin-independent and -dependent Wingless and Int-1 (WNT) pathways and the termination of peroxisome proliferator-activated receptor γ (PPARγ) signal transduction. Several atherosclerotic plaque studies confirmed the differential activity of PPARγ and the WNT signaling pathways in VC. Notably, the actively regulated β-catenin-dependent and -independent WNT signals increase the osteochondrogenic transformation of VSMC through the up-regulation of the osteochondrogenic transcription factors SRY-box transcription factor 9 (SOX9) and runt-related transcription factor 2 (RUNX2). In addition, we have reported studies showing that WNT signaling pathways may be antagonized by PPARγ activation via the expression of different families of WNT inhibitors and through its direct interaction with β-catenin. In this review, we summarize the existing knowledge on WNT and PPARγ signaling and their interplay during the osteochondrogenic differentiation of VSMC in VC. Finally, we discuss knowledge gaps on this interplay and its possible clinical impact.

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