Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells.
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 globalAtf4KO, smooth muscle cell-specific (SMC-specific)Atf4KO, and transgenic (TG) mouse models. Reduced expression of ATF4 in global ATF4-haplodeficient and SMC-specificAtf4KO mice reduced medial and atherosclerotic calcification under normal kidney and CKD conditions. In contrast, increased expression of ATF4 in SMC-specificAtf4TG 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.
Division of Renal Diseases and Hypertension, Department of Medicine, and.
Masashi
M
Masuda
Division of Renal Diseases and Hypertension, Department of Medicine, and.
Shinobu
S
Miyazaki-Anzai
Division of Renal Diseases and Hypertension, Department of Medicine, and.
Audrey L
AL
Keenan
Division of Renal Diseases and Hypertension, Department of Medicine, and.
Yuji
Y
Shiozaki
Division of Renal Diseases and Hypertension, Department of Medicine, and.
Kayo
K
Okamura
Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado, USA.
Wallace S
WS
Chick
Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado, USA.
Kristina
K
Williams
Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado, USA.
Xiaoyun
X
Zhao
Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA.
Shaikh Mizanoor
SM
Rahman
Division of Cardiology, Department of Medicine, University of California, Los Angeles, California, USA.
Yin
Y
Tintut
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
Christopher M
CM
Adams
Division of Renal Diseases and Hypertension, Department of Medicine, and.
Makoto
M
Miyazaki
D051701:Activating Transcription Factor 4 / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D016623:Ion Pumps / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009130:Muscle, Smooth; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D061205:Vascular Calcification / Q000378:metabolism* / Q000473:pathology
C081452:Atf4 protein, mouse; D016623:Ion Pumps; D051701:Activating Transcription Factor 4