Inhibition of Bone Morphogenetic Protein Signal Transduction Prevents the Medial Vascular Calcification Associated with Matrix Gla Protein Deficiency

Malhotra, Rajeev; Burke, Megan F.; Martyn, Trejeeve; Shakartzi, Hannah R.; Thayer, Timothy E.; O’Rourke, Caitlin; Li, Pingcheng; Derwall, Matthias; Spagnolli, Ester; Kolodziej, Starsha; Hoeft, Konrad; Mayeur, Claire; Jiramongkolchai, Pawina; Kumar, Ravindra; Buys, Emmanuel; Yu, Paul B.; Bloch, Kenneth D.; Bloch, Donald B.

doi:10.1371/journal.pone.0117098

Cited by 61 publications

(63 citation statements)

References 55 publications

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“…In our study, BMP-4 acted as an inductive factor of EndMTs in MGP deficiency, which is consistent with results from other investigators 6, 53 . The BMPs elicit their activity through ligand-initiated heterodimerization of BMP type II receptors (BMPRII) and type I receptors referred to as activin receptor-like kinase (ALK) 1, 2, 3, and 6 54 .…”

Section: Discussionsupporting

confidence: 94%

Serine Protease Activation Essential for Endothelial–Mesenchymal Transition in Vascular Calcification

Yao

Guihard

Blázquez‐Medela

et al. 2015

Circulation Research

125

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Rationale Endothelial cells have the ability to undergo endothelial-mesenchymal transitions (EndMTs), by which they acquire a mesenchymal phenotype and stem-cell like characteristics. We previously found that EndMTs ocurred in the endothelium deficient in matrix Gla protein (MGP) enabling endothelial cells to contribute cells to vascular calcification. However, the mechanism responsible for initiating EndMTs is not fully understood. Objective To determine the role of specific serine proteases and sex determining region Y-box 2 (Sox2) in the initiation of EndMTs. Methods and Results In this study, we used in vivo and in vitro models of vascular calcification to demonstrate that serine proteases and Sox2 are essential for the initiation of EndMTs in MGP-deficient endothelium. We showed that expression of a group of specific serine proteases was highly induced in endothelial cells at sites of vascular calcification in Mgp null aortas. Treatment with serine protease inhibitors decreased both stem-cell marker expression and vascular calcification. In human aortic endothelial cells, this group of serine proteases also induced EndMTs, and the activation of proteases was mediated by Sox2. Knockdown of the serine proteases or Sox2 diminished EndMTs and calcification. Endothelial-specific deletion of Sox2 decreased expression of stem-cell markers and aortic calcification in MGP-deficient mice. Conclusions Our results suggest that Sox2-mediated activation of specific serine proteases is essential for initiating EndMTs, and thus, may provide new therapeutic targets for treating vascular calcification.

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Section: Discussionsupporting

confidence: 94%

Serine Protease Activation Essential for Endothelial–Mesenchymal Transition in Vascular Calcification

Yao

Guihard

Blázquez‐Medela

et al. 2015

Circulation Research

125

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“…This distribution of calcification is similar to that seen in the MGP-deficient mouse model of vascular calcification [25]. In this model, inhibition of BMP signal transduction, using the small molecule inhibitor LDN-193189, decreased the extent of vascular calcification, suggesting that BMP signaling has an important role in disease pathogenesis [13, 15]. …”

Section: Discussionsupporting

confidence: 67%

Increased Bone Morphogenetic Protein Signaling in the Cutaneous Vasculature of Patients with Calciphylaxis

et al. 2017

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Background: The objective of this study was to investigate the role of bone morphogenetic protein (BMP) signal transduction in the pathogenesis of calciphylaxis. Methods: Skin biopsy specimens were obtained from 18 patients with, and 12 patients without, calciphylaxis. Tissue sections were stained with antibodies directed against BMP effector proteins phosphorylated-SMAD (p-SMAD) 1/5/9, inhibitor of DNA 1 (Id1), inhibitor of DNA 3 (Id3), and Runx2. The intensity of staining was scored semi-quantitatively as strong versus weak or absent. Results: Of the 18 patients with calciphylaxis (mean age: 59 ± 8 years), 9 were women and 15 had end-stage renal disease. Of the 12 control patients (mean age: 57 ± 10 years), 8 were women and 8 had end-stage renal disease. Strong staining for p-SMAD 1/5/9 was detected in blood vessels from all calciphylaxis patients. In 1 patient with calciphylaxis, strong staining for p-SMAD 1/5/9 was detected in a blood vessel that did not have evidence of calcification. Id1 and Id3 immunoreactivity was detected in blood vessels from all 12 patients with calciphylaxis that were tested. Runx2 staining was detected in all 6 patients with calciphylaxis who were tested. p-SMAD 1/5/9 immunoreactivity was weak or absent in blood vessels of 10 of the 12 control samples. Conclusions: The BMP signal transduction pathway is activated in the cutaneous vasculature of calciphylaxis patients. The ability to detect p-SMAD 1/5/9, Id1, and Id3 in cutaneous vasculature may assist in the diagnosis of calciphylaxis. As BMP signaling inhibitors become available, this pathway may serve as a future therapeutic target for calciphylaxis.

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“…32 Circulating levels of dp-ucMGP do not affect vascular calcifications because dp-ucMGP is biologically inactive and not able to bind calcification and bone morphogenetic protein 2. 37,38 However, low levels, as seen with vitamin K supplementation, reflect strong MGP carboxylation and so maximum inhibition of calcification in the arterial wall. 27 Two ongoing randomized trials currently explore whether vitamin K supplementation decreases arterial and valvular calcifications in hemodialysis patients.…”

Section: Discussionmentioning

confidence: 99%

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

et al. 2015

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Increased pulse wave velocity (PWV) is the gold standard in assessing stiffening of the aorta.1 As shown by 3 population studies, all including over thousand participants, PWV refines risk stratification above and beyond traditional cardiovascular risk factors. In multivariable-adjusted analyses, per one standard deviation (SD) increment in PWV, cardiovascular mortality increased by 20% and 60% in a Danish and Taiwanese population samples, respectively.2,3 The Framingham heart study found that one standard deviation increment of PWV was associated with a 48% increase in cardiovascular disease risk. 4 Matrix Gla-protein (MGP) is acting as a strong inhibitor of soft tissue calcification. 5,6 MGP knockout mice develop massive vascular calcification in their first weeks of life and die within 2 months of vessels rupture.7 MGP is expressed primarily by chondrocytes and vascular smooth muscle cells. 8,9 To acquire its full calcification inhibitory activity, MGP needs to undergo 2 post-translational modifications: glutamate carboxylation and serine phosphorylation. Both modifications are not exerted completely, so theoretically, 4 different MGP conformations can be found: unmodified and Abstract-Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality.Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based crosssectional study in Switzerland. Dp-ucMGP was quantified in plasma by sandwich ELISA. Aortic PWV was determined by applanation tonometry using carotid and femoral pulse waveforms. Multiple regression analysis was performed to estimate associations between PWV and dp-ucMGP adjusting for age, renal function, and other cardiovascular risk factors. We included 1001 participants in our analyses (475 men and 526 women). Mean values were 7.87±2.10 m/s for PWV and 0.43±0.20 nmol/L for dp-ucMGP. PWV was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, height, systolic and diastolic blood pressure (BP), heart rate, renal function, low-and high-density lipoprotein, glucose, smoking status, diabetes mellitus, BP and cholesterol lowering drugs, and history of cardiovascular disease (P≤0.01). In conclusion, high levels of dp-ucMGP are independently and positively associated with arterial stiffness after adjustment for common cardiovascular risk factors, renal function, and age. inactive as desphospho-uncarboxylated MGP (dp-ucMGP), only phosphorylated, only carboxylated, and finally fully modified and active as phosphorylated and carboxylated MGP. 10,11 Carboxylation of MGP is a vitamin K-dependent process: vitamin K hydroquinone, a vitamin K m...

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Inhibition of Bone Morphogenetic Protein Signal Transduction Prevents the Medial Vascular Calcification Associated with Matrix Gla Protein Deficiency

Cited by 61 publications

References 55 publications

Serine Protease Activation Essential for Endothelial–Mesenchymal Transition in Vascular Calcification

Serine Protease Activation Essential for Endothelial–Mesenchymal Transition in Vascular Calcification

Increased Bone Morphogenetic Protein Signaling in the Cutaneous Vasculature of Patients with Calciphylaxis

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

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