scholarly journals Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Setareh Orth-Alampour ◽  
Nathalie Gayrard ◽  
Silvia Salem ◽  
Shruti Bhargava ◽  
Vera Jankowski ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Active Site ◽  
Chromogranin A ◽  
Adrenal Glands ◽  
Calcium Content ◽  
Mesenchymal Cell ◽  
Vascular Wall ◽  
Osteoblastic Differentiation ◽  
Culture Conditions ◽  
Water Metabolism

AbstractThe adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the “calcification blocking factor” (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.

P1237TISSUE-NONSPECIFIC ALKALINE PHOSPHATASE, A CULPRIT DURING ARTERIAL MEDIA CALCIFICATION BUT INDISPENSABLE DURING PHYSIOLOGICAL BONE FORMATION/-MINERALIZATION IN RATS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Britt Opdebeeck ◽  
José Millan Luis ◽  
Anthony Pinkerton ◽  
Anja Verhulst ◽  
Patrick D'Haese ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Bone Formation ◽  
Vascular Calcification ◽  
Rat Model ◽  
Bone Mineralization ◽  
Calcium Content ◽  
Marker Genes ◽  
Peripheral Arteries ◽  
Calcium Phosphorus ◽  
Chondrogenic Marker

Abstract Background and Aims Vascular media calcification is frequently seen in elderly and patients with chronic kidney disease (CKD), diabetes and osteoporosis. Pyrophosphate is a well-known calcification inhibitor that binds to nascent hydroxyapatite crystals and prevents further incorporation of inorganic phosphate into these crystals. However, the enzyme tissue-nonspecific alkaline phosphatase (TNAP), which is highly expressed in calcified arteries, degrades extracellular pyrophosphate into phosphate ions, by which pyrophosphate loses its ability to block vascular calcification. Here, we aimed to evaluate whether a TNAP inhibitor is able to prevent the development of arterial calcification in a rat model of warfarin-induced vascular calcification. Method To induce vascular calcification, rats received a diet containing 0.30% warfarin and 0.15% vitamin K1 throughout the entire study and were subjected to the following daily treatments: (i) vehicle (n=10) or (ii) 10 mg/kg/day TNAP-inhibitor (n=10) administered via an intraperitoneal catheter from start of the study until sacrifice at week 7. Calcium, phosphorus and parathyroid hormone (PTH) levels were determined in serum samples as these are important determinants of vascular calcification. As TNAP is also expressed in the liver, serum alanine aminotransferase (ALT) and aspartate (AST) levels were analyzed. At sacrifice, vascular calcification was evaluated by measurement of the total calcium content in the arteries and quantification of the area % calcification on Von Kossa stained sections of the aorta. The mRNA expression of osteo/chondrogenic marker genes (runx2, TNAP, SOX9, collagen 1 and collagen 2) was analyzed in the aorta by qPCR to verify whether vascular smooth muscle cells underwent reprogramming towards bone-like cells. Bone histomorphometry was performed on the left tibia to measure static and dynamic bone parameters as TNAP also regulates physiological bone mineralization. Results No differences in serum calcium, phosphorus and PTH levels was observed between both study groups. Warfarin exposure resulted in distinct calcification in the aorta and peripheral arteries. Daily dosing with the TNAP inhibitor (10 mg/kg/day) for 7 weeks significantly reduced vascular calcification as indicated by a significant decrease in calcium content in the aorta (vehicle 3.84±0.64 mg calcium/g wet tissue vs TNAP inhibitor 0.70±0.23 mg calcium/g wet tissue) and peripheral arteries and a distinct reduction in area % calcification on Von Kossa stained aortic sections as compared to vehicle condition. The inhibitory effects of SBI-425 on vascular calcification were without altering serum liver markers ALT and AST levels. Furthermore, TNAP-inhibitor SBI-425 did not modulate the mRNA expression of osteo/chondrogenic marker genes runx2, TNAP, SOX9, collagen 1 and 2. Dosing with SBI-425 resulted in decreased bone formation rate and mineral apposition rate, and increased osteoid maturation time and this without significant changes in osteoclast- and eroded perimeter. Conclusion Dosing with TNAP inhibitor SBI-425 significantly reduced the calcification in the aorta and peripheral arteries of a rat model of warfarin-induced vascular calcification and this without affecting liver function. However, suppression of TNAP activity should be limited in order to maintain adequate physiological bone mineralization.

Ligustrazine activate the PPAR-γ pathway and play a protective role in vascular calcification

Vascular ◽  
2021 ◽  
pp. 170853812110514
Author(s):  
Hui Li ◽  
Min Yang
Keyword(s):  
Vascular Calcification ◽  
Chondrogenic Differentiation ◽  
Calcium Content ◽  
Protective Role ◽  
Peroxisome Proliferation ◽  
Rt Pcr ◽  
Alizarin Red ◽  
Ppar Γ ◽  
Related Proteins

Objective The purpose of this study was to explore the role of ligustrazine in vascular calcification. Methods After β-GP stimulation, vascular smooth muscle cells (VSMCs) were detected by Alizarin Red Staing staining. Calcium content and alkaline phosphatase (ALP) activity were detected by intracellular calcium assay kit and ALP assay kit, respectively. The expression of peroxisome proliferation-activated receptor (PPAR-γ) pathway–related proteins was detected by Western blot. PPAR-γ, MSX2, osteopontin (OPN), sclerostin, and BGP were detected by RT-PCR. Results β-GP induced the decreased activity and expression of PPAR-γ and ALP in VSMCs, while ligustrazine activated the expression of PPAR-γ. Through activation of PPAR-γ, ligustrazine decreased β-GP–induced VSMC calcification, decreased the expression of markers of osteogenesis and chondrogenic differentiation, and increased the expression of VSMC markers. Conclusion Ligustrazine activates the PPAR-γ pathway and plays a protective role in vascular calcification.

scholarly journals Triptolide Attenuates Vascular Calcification by Upregulating Expression of miRNA-204

2021 ◽  
Vol 11 ◽  
Author(s):  
Yu-qiang Pei ◽  
Yong-qiu Zheng ◽  
Yao-dong Ding ◽  
Qi-xiang Xu ◽  
Di Cao ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Calcium Content ◽  
Rat Aorta ◽  
Protective Role ◽  
Bone Morphogenetic Protein 2 ◽  
Dependent Manner ◽  
Protective Effects ◽  
Alp Activity

Background: Triptolide (TP), a naturally derived compound from Tripterygium wilfordii, has been proven effective in protecting against cardiovascular system, but the molecular mechanisms underlying its protective effects are poorly understood. In the current study, we sought to test the potential protective role of TP in the regulation of vascular calcification in a rat model and explore whether TP attenuates medial vascular calcification by upregulating miRNA-204.Methods: Vitamin D3 plus nicotine (VDN) was used to induce a vascular calcification (VC) model of rat aorta. Von Kossa and Hematoxylin-Eosin staining were applied to assess the degree of calcification of rat aortas. Calcium content and alkaline phosphatase activity were measured. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was applied to quantify miRNA-204 expression. The localization of runt-related transcription factor-2 (RUNX2) and bone morphogenetic protein-2 (BMP2) expressions were detected by immunohistochemistry and western blotting.Results: Administration of TP greatly reduced vascular calcification in a dose-dependent manner compared with VC controls. The increase in ALP activity and calcium content was ameliorated by TP. Moreover, protein expression levels of BMP2 and RUNX2 were significantly reduced in calcified aortas. MiRNA-204 expression was increased in the TP-treated groups compared with VC controls and the effects of TP were reversed by the intravenous injection of miRNA-204-interfering lentivirus. However, the miRNA-204-overexpressing lentivirus had no additional effects on ALP activity, calcium content, BMP2 and RUNX2 expressions compared with those from TP group.Conclusion: TP inhibited BMP2 and RUNX2 expression and attenuated vascular calcification via upregulating the level of miRNA-204. TP appears to be a potential new therapeutic option for treating vascular calcification.

scholarly journals Mice overexpressing chromogranin A display hypergranulogenic adrenal glands with attenuated ATP levels contributing to the hypertensive phenotype

2018 ◽  
Vol 36 (5) ◽  
pp. 1115-1128
Author(s):  
Saiful A. Mir ◽  
Ying Li ◽  
Jacob D. Story ◽  
Soma Bal ◽  
Linda Awdishu ◽  
...  
Keyword(s):  
Chromogranin A ◽  
Adrenal Glands ◽  
Atp Levels

scholarly journals Optimisation of cell and ex vivo culture conditions to study vascular calcification

PLoS ONE ◽  
2020 ◽  
Vol 15 (3) ◽  
pp. e0230201 ◽  
Author(s):  
Nathalie Gayrard ◽  
Karen Muyor ◽  
Cécile Notarnicola ◽  
Flore Duranton ◽  
Bernard Jover ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Ex Vivo ◽  
Culture Conditions ◽  
Ex Vivo Culture

Osteoblastic differentiation potential of human amniotic fluid-derived mesenchymal stem cells in different culture conditions

2018 ◽  
Vol 120 (8) ◽  
pp. 701-712 ◽  
Author(s):  
Tanongsak Laowanitwattana ◽  
Sirinda Aungsuchawan ◽  
Suteera Narakornsak ◽  
Runchana Markmee ◽  
Waleephan Tancharoen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Amniotic Fluid ◽  
Osteoblastic Differentiation ◽  
Culture Conditions ◽  
Human Amniotic Fluid ◽  
Differentiation Potential

scholarly journals Role Of Vitamin K Therapy In Prevention Of Vascular Calcification In Chronic Kidney Disease

2020 ◽  
Vol 2 (4) ◽  
Author(s):  
Mohamed Farouk Ibrahim Mosa ◽  
Ahmed Kamal Harfoosh
Keyword(s):  
Vascular Calcification ◽  
Vitamin K ◽  
Vascular Wall ◽  
Matrix Gla Protein ◽  
Oral Vitamin ◽  
Inhibitory Protein ◽  
Baseline Levels ◽  
One Year ◽  
Stage Renal Disease ◽  
End Stage

Introduction: Matrix Gla protein (MGP) is a central calcification inhibitor of vascular wall. The biological activation of the calcification-inhibitory protein MGP can be achieved by simple administration of oral vitamin K. Aim: The study was conducted to assess the effect of vitamin k supplementation on vascular calcification and to evaluate its effect on MGA in hemodialysis patients. Materials and Methods: Forty adult patients with end stage renal disease (ESRD) on regular hemodialysis sessions, thrice weekly, were enrolled in the study and were randomly assigned into two groups. Vitamin K group consisted of 20 patients were given oral vitamin K at 10 mg after each session of dialysis for a duration of one year. No-Vitamin K group included 20 patients didn’t receive vitamin K. All patients were subjected to the following: Matrix Gla protein (MGP), in addition to, plain digital abdominal x-ray and doppler ultrasound. Results: After one-year of vitamin K supplementation, a significant increase in MGP levels in Vitamin K group (75.7±26 ng/mL) were noticed. There were no significant changes in CIMT and AACS in Vitamin K group after vitamin K supplementation in compared to their baseline levels, while the CIMT and AACS were significantly increased in No-Vitamin K group in compared to their baseline levels. Conclusion: Vitamin K supplementation could not stop vascular calcifications but significantly attenuate their progression.

scholarly journals Secreted Frizzled-Related Protein 5 Ameliorates Vascular Calcification in a Rat Model of Chronic Kidney Disease through the Wnt/β-Catenin Pathway

2021 ◽  
pp. 1-10
Author(s):  
Dai Deng ◽  
Xue Han ◽  
Zongli Diao ◽  
Wenhu Liu
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Rat Model ◽  
In Vitro Study ◽  
Calcium Content ◽  
Control Group ◽  
Related Protein ◽  
High Phosphate

<b><i>Introduction:</i></b> Vascular calcification (VC) is highly prevalent and a major cardiovascular risk factor in chronic kidney disease (CKD) patients. Secreted frizzled-related protein 5 (SFRP5), an inhibitor of the Wnt pathway, is an adipokine with a positive effect on metabolic and cardiovascular diseases. Our previous in vitro study showed that SFRP5 attenuates high phosphate-induced calcification in vascular smooth muscle cells by inhibiting the Wnt/β-catenin pathway. Therefore, we hypothesized that SFRP5 may protect against CKD-associated VC (CKD-VC) through the same signalling. <b><i>Methods:</i></b> The rat model of CKD with VC was induced by 0.75% adenine combined with 1.8% high phosphate diet, which were administered with adenovirus vectors of SFRP5. We evaluated the SFRP5 effect on VC by von Kossa staining and calcium content analysis and osteogenic markers by immunohistochemistry and Western blot. The components of Wnt/ß-catenin signalling were also evaluated. <b><i>Results:</i></b> SFRP5 local and serum levels were significantly decreased in the CKD-VC rat model compared with the control group. Adenovirus-mediated overexpression of SFRP5 significantly inhibited VC, which was due to suppression of CKD-induced expression of calcification and osteoblastic markers. Additionally, SFRP5 abrogated activation of the Wnt/β-catenin pathway that plays a major role in the pathogenesis of VC. The specificity of SFRP5 for inhibition of VC was confirmed using an empty adenovirus as a control. <b><i>Conclusion:</i></b> Our results suggest that SFRP5 ameliorates VC of CKD rats by inhibiting the expression of calcification and osteoblastic markers as well as the Wnt/β-catenin pathway. Collectively, this study suggests that SFRP5 is a potential therapeutic target in CKD-VC.

scholarly journals Epidemiological Research Advances in Vascular Calcification in Diabetes

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Haipeng Yao ◽  
Zhen Sun ◽  
Guangyao Zang ◽  
Lili Zhang ◽  
Lina Hou ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Ethnic Differences ◽  
Cardiovascular Events ◽  
Arterial Wall ◽  
Basic Research ◽  
Vascular Wall ◽  
Vascular Bed ◽  
Evaluation Strategies ◽  
Patients With Diabetes ◽  
Clinical Transformation

Vascular calcification is the transformation of arterial wall mesenchymal cells, particularly smooth muscle cells (SMCs), into osteoblast phenotypes by various pathological factors. Additionally, vascular transformation mediates the abnormal deposition of calcium salts in the vascular wall, such as intimal and media calcification. Various pathological types have been described, such as calcification and valve calcification. The incidence of vascular calcification in patients with diabetes is much higher than that in nondiabetic patients, representing a critical cause of cardiovascular events in patients with diabetes. Because basic research on the clinical transformation of vascular calcification has yet to be conducted, this study systematically expounds on the risk factors for vascular calcification, vascular bed differences, sex differences, ethnic differences, diagnosis, severity assessments, and treatments to facilitate the identification of a new entry point for basic research and subsequent clinical transformation regarding vascular calcification and corresponding clinical evaluation strategies.

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