Journal article
Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells
JCI insight, Vol.1(18), pp.e88646-e88646
11/03/2016
DOI: 10.1172/jci.insight.88646
PMCID: PMC5085604
PMID: 27812542
Abstract
Emerging evidence indicates that upregulation of the ER stress–induced pro-osteogenic transcription factor ATF4 plays an important role in vascular calcification, a common complication in patients with aging, diabetes, and chronic kidney disease (CKD). In this study, we demonstrated the pathophysiological role of ATF4 in vascular calcification using global
Atf4
KO, smooth muscle cell–specific (SMC-specific)
Atf4
KO, and transgenic (TG) mouse models. Reduced expression of ATF4 in global ATF4-haplodeficient and SMC-specific
Atf4
KO mice reduced medial and atherosclerotic calcification under normal kidney and CKD conditions. In contrast, increased expression of ATF4 in SMC-specific
Atf4
TG mice caused severe medial and atherosclerotic calcification. We further demonstrated that ATF4 transcriptionally upregulates the expression of type III sodium-dependent phosphate cotransporters (PiT1 and PiT2) by interacting with C/EBPβ. These results demonstrate that the ER stress effector ATF4 plays a critical role in the pathogenesis of vascular calcification through increased phosphate uptake in vascular SMCs.
Details
- Title: Subtitle
- Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells
- Creators
- Masashi Masuda - Division of Renal Diseases and Hypertension, Department of Medicine, andShinobu Miyazaki-Anzai - Division of Renal Diseases and Hypertension, Department of Medicine, andAudrey L Keenan - Division of Renal Diseases and Hypertension, Department of Medicine, andYuji Shiozaki - Division of Renal Diseases and Hypertension, Department of Medicine, andKayo Okamura - Division of Renal Diseases and Hypertension, Department of Medicine, andWallace S Chick - Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado, USAKristina Williams - Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado, USAXiaoyun Zhao - Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado, USAShaikh Mizanoor Rahman - Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USAYin Tintut - Division of Cardiology, Department of Medicine, University of California, Los Angeles, California, USAChristopher M Adams - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAMakoto Miyazaki - Division of Renal Diseases and Hypertension, Department of Medicine, and
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.1(18), pp.e88646-e88646
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.88646
- PMID
- 27812542
- PMCID
- PMC5085604
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Language
- English
- Date published
- 11/03/2016
- Academic Unit
- Molecular Physiology and Biophysics; Internal Medicine
- Record Identifier
- 9984025597302771
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