TDAG51 (T-Cell Death-Associated Gene 51) Is a Key Modulator of Vascular Calcification and Osteogenic Transdifferentiation of Arterial Smooth Muscle Cells

被引：13

作者：

Platko, Khrystyna ^{[1
]}

Lebeau, Paul F. ^{[1
]}

Gyulay, Gabriel ^{[1
]}

Lhotak, Sarka ^{[1
]}

MacDonald, Melissa E. ^{[1
]}

Pacher, Giusepina ^{[1
]}

Hyun Byun, Jae ^{[1
]}

Boivin, Felix J. ^{[3
]}

Igdoura, Suleiman A. ^{[3
,4
]}

Cutz, Jean-Claude ^{[2
]}

Bridgewater, Darren ^{[3
]}

Ingram, Alistair J. ^{[1
]}

Krepinsky, Joan C. ^{[1
]}

Austin, Richard C. ^{[1
]}

机构：

[1] McMaster Univ, Dept Med, Div Nephrol, Hamilton, ON, Canada

[2] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada

[3] McMaster Univ, Med Ctr, Dept Pathol & Mol Med, Hamilton, ON, Canada

[4] McMaster Univ, Med Ctr, Dept Biol, Hamilton, ON, Canada

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2020年 / 40卷 / 07期

基金：

加拿大健康研究院;

关键词：

hyperphosphatemia; inorganic phosphate transporter; osteoblasts; risk factor; vascular calcification; vascular smooth muscle cells; DEPENDENT PHOSPHATE COTRANSPORTERS; ENDOPLASMIC-RETICULUM STRESS; MEDIAL CALCIFICATION; SERUM PHOSPHORUS; KIDNEY-DISEASE; BONE-FORMATION; UP-REGULATION; VITAMIN-D; RUNX2; EXPRESSION;

D O I：

10.1161/ATVBAHA.119.313779

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective: Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced chronic kidney disease and is now recognized as an important predictor and independent risk factor for cardiovascular and all-cause mortality in these patients. VC in chronic kidney disease is triggered by the transformation of vascular smooth muscle cells (VSMCs) into osteoblasts as a consequence of elevated circulating inorganic phosphate (P-i) levels, due to poor kidney function. The objective of our study was to investigate the role of TDAG51 (T-cell death-associated gene 51) in the development of medial VC. Methods and Results: Using primary mouse and human VSMCs, we found that TDAG51 is induced in VSMCs by P(i)and is expressed in the medial layer of calcified human vessels. Furthermore, the transcriptional activity of RUNX2 (Runt-related transcription factor 2), a well-established driver of P-i-mediated VC, is reduced in TDAG51(-/-)VSMCs. To explain these observations, we identified that TDAG51(-/-)VSMCs express reduced levels of the type III sodium-dependent P(i)transporter, Pit-1, a solute transporter, a solute transporter, a solute transporter responsible for cellular P(i)uptake. Significantly, in response to hyperphosphatemia induced by vitamin D-3, medial VC was attenuated in TDAG51(-/-)mice. Conclusions: Our studies highlight TDAG51 as an important mediator of P-i-induced VC in VSMCs through the downregulation of Pit-1. As such, TDAG51 may represent a therapeutic target for the prevention of VC and cardiovascular disease in patients with chronic kidney disease.

引用

页码：1664 / 1679

页数：16

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