Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate
Vascular calcification is a life-threatening clinical condition in chronic kidney disease (CKD) and is associated with reduced zinc serum levels. Anemia is another frequent complication of CKD. Hypoxia-inducible factor (HIF) stabilizers, also known as HIF prolyl hydroxylase inhibitors (PHI), are pro...
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Frontiers Media S.A.
2020-01-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.01584/full |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Annamária Nagy Annamária Nagy Dávid Pethő Dávid Pethő Tamás Gáll Tamás Gáll Erzsébet Zavaczki Erzsébet Zavaczki Erzsébet Zavaczki Mónika Nyitrai Mónika Nyitrai József Posta Abolfazl Zarjou Anupam Agarwal György Balla György Balla József Balla József Balla |
spellingShingle |
Annamária Nagy Annamária Nagy Dávid Pethő Dávid Pethő Tamás Gáll Tamás Gáll Erzsébet Zavaczki Erzsébet Zavaczki Erzsébet Zavaczki Mónika Nyitrai Mónika Nyitrai József Posta Abolfazl Zarjou Anupam Agarwal György Balla György Balla József Balla József Balla Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate Frontiers in Physiology VSMC vascular calcification phosphate Zn supplementation Pi prolyl hydroxylase inhibitor |
author_facet |
Annamária Nagy Annamária Nagy Dávid Pethő Dávid Pethő Tamás Gáll Tamás Gáll Erzsébet Zavaczki Erzsébet Zavaczki Erzsébet Zavaczki Mónika Nyitrai Mónika Nyitrai József Posta Abolfazl Zarjou Anupam Agarwal György Balla György Balla József Balla József Balla |
author_sort |
Annamária Nagy |
title |
Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate |
title_short |
Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate |
title_full |
Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate |
title_fullStr |
Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate |
title_full_unstemmed |
Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate |
title_sort |
zinc inhibits hif-prolyl hydroxylase inhibitor-aggravated vsmc calcification induced by high phosphate |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2020-01-01 |
description |
Vascular calcification is a life-threatening clinical condition in chronic kidney disease (CKD) and is associated with reduced zinc serum levels. Anemia is another frequent complication of CKD. Hypoxia-inducible factor (HIF) stabilizers, also known as HIF prolyl hydroxylase inhibitors (PHI), are promising candidates to treat CKD-associated anemia by increasing erythropoietin synthesis. Recent evidence suggests that HIFs play a pivotal role in vascular calcification. Our study explored feasible impacts of HIF PHI on phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs) and tested whether zinc might inhibit this mineralization process. Treatment of VSMCs with PHI aggravated Pi-induced calcium deposition and Pi uptake. PHI promoted Pi-induced loss of smooth muscle cell markers (ACTA-2, MYH11, SM22α) and enhanced osteochondrogenic gene expression (Msx-2, BMP-2, Sp7) triggering osteochondrogenic phenotypic switch of VSMCs. These effects of PHI paralleled with increased pyruvate dehydrogenase kinase 4 (PDK4) expression, decreased Runx2 Ser451 phosphorylation, and reduced cell viability. Zinc inhibited Pi-induced mineralization of VSMCs in a dose-dependent manner and also attenuated the pro-calcification effect of PHI in Pi-induced mineralization. Zinc inhibited osteochondrogenic phenotypic switch of VSMCs reflected by lowering Pi uptake, decreasing the expressions of Msx-2, BMP-2, and Sp7 as well as the loss of smooth muscle cell-specific markers. Zinc preserved phosphorylation state of Runx2 Ser451, decreased PDK4 level, and restored cell viability. PHI alone reduced the expression of smooth muscle markers without inducing mineralization, which was also inhibited by zinc. In addition, we observed a significantly lower serum zinc level in CKD as well as in patients undergoing carotid endarterectomy compared to healthy individuals. Conclusion - PHI promoted the loss of smooth muscle markers and augmented Pi-induced osteochondrogenic phenotypic switch leading to VSMCs calcification. This mineralization process was attenuated by zinc. Enhanced vascular calcification is a potential risk factor during PHI therapy in CKD which necessitates the strict follow up of vascular calcification and zinc supplementation. |
topic |
VSMC vascular calcification phosphate Zn supplementation Pi prolyl hydroxylase inhibitor |
url |
https://www.frontiersin.org/article/10.3389/fphys.2019.01584/full |
work_keys_str_mv |
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doaj-51453d52e2204cfc8742d341cda4206d2020-11-25T02:14:57ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2020-01-011010.3389/fphys.2019.01584483794Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High PhosphateAnnamária Nagy0Annamária Nagy1Dávid Pethő2Dávid Pethő3Tamás Gáll4Tamás Gáll5Erzsébet Zavaczki6Erzsébet Zavaczki7Erzsébet Zavaczki8Mónika Nyitrai9Mónika Nyitrai10József Posta11Abolfazl Zarjou12Anupam Agarwal13György Balla14György Balla15József Balla16József Balla17Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, HungaryKálmán Laki Doctoral School, University of Debrecen, Debrecen, HungaryDepartment of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, HungaryKálmán Laki Doctoral School, University of Debrecen, Debrecen, HungaryHAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Debrecen, HungaryDepartment of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, HungaryDepartment of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, HungaryKálmán Laki Doctoral School, University of Debrecen, Debrecen, HungaryHAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Debrecen, HungaryDepartment of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, HungaryHAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Debrecen, HungaryDepartment of Inorganic and Analytical Chemistry, UD Faculty of Science and Technology, University of Debrecen, Debrecen, HungaryNephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United StatesNephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United StatesHAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Debrecen, HungaryDepartment of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, HungaryDepartment of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, HungaryHAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Debrecen, HungaryVascular calcification is a life-threatening clinical condition in chronic kidney disease (CKD) and is associated with reduced zinc serum levels. Anemia is another frequent complication of CKD. Hypoxia-inducible factor (HIF) stabilizers, also known as HIF prolyl hydroxylase inhibitors (PHI), are promising candidates to treat CKD-associated anemia by increasing erythropoietin synthesis. Recent evidence suggests that HIFs play a pivotal role in vascular calcification. Our study explored feasible impacts of HIF PHI on phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs) and tested whether zinc might inhibit this mineralization process. Treatment of VSMCs with PHI aggravated Pi-induced calcium deposition and Pi uptake. PHI promoted Pi-induced loss of smooth muscle cell markers (ACTA-2, MYH11, SM22α) and enhanced osteochondrogenic gene expression (Msx-2, BMP-2, Sp7) triggering osteochondrogenic phenotypic switch of VSMCs. These effects of PHI paralleled with increased pyruvate dehydrogenase kinase 4 (PDK4) expression, decreased Runx2 Ser451 phosphorylation, and reduced cell viability. Zinc inhibited Pi-induced mineralization of VSMCs in a dose-dependent manner and also attenuated the pro-calcification effect of PHI in Pi-induced mineralization. Zinc inhibited osteochondrogenic phenotypic switch of VSMCs reflected by lowering Pi uptake, decreasing the expressions of Msx-2, BMP-2, and Sp7 as well as the loss of smooth muscle cell-specific markers. Zinc preserved phosphorylation state of Runx2 Ser451, decreased PDK4 level, and restored cell viability. PHI alone reduced the expression of smooth muscle markers without inducing mineralization, which was also inhibited by zinc. In addition, we observed a significantly lower serum zinc level in CKD as well as in patients undergoing carotid endarterectomy compared to healthy individuals. Conclusion - PHI promoted the loss of smooth muscle markers and augmented Pi-induced osteochondrogenic phenotypic switch leading to VSMCs calcification. This mineralization process was attenuated by zinc. Enhanced vascular calcification is a potential risk factor during PHI therapy in CKD which necessitates the strict follow up of vascular calcification and zinc supplementation.https://www.frontiersin.org/article/10.3389/fphys.2019.01584/fullVSMCvascular calcificationphosphateZn supplementationPiprolyl hydroxylase inhibitor |