Vascular calcification is a common feature of major cardiovascular diseases. Extracellular vesicles participate in the formation of microcalcifications that are implicated in atherosclerotic plaque rupture; however, the mechanisms that regulate formation of calcifying extracellular vesicles remain obscure. Here, we have demonstrated that sortilin is a key regulator of smooth muscle cell (SMC) calcification via its recruitment to extracellular vesicles. Sortilin localized to calcifying vessels in human and mouse atheromata and participated in formation of microcalcifications in SMC culture. Sortilin regulated the loading of the calcification protein tissue nonspecific alkaline phosphatase (TNAP) into extracellular vesicles, thereby conferring its calcification potential. Furthermore, SMC calcification required Rab11-dependent trafficking and FAM20C/casein kinase 2–dependent C-terminal phosphorylation of sortilin. In a murine model,
Claudia Goettsch, Joshua D. Hutcheson, Masanori Aikawa, Hiroshi Iwata, Tan Pham, Anders Nykjaer, Mads Kjolby, Maximillian Rogers, Thomas Michel, Manabu Shibasaki, Sumihiko Hagita, Rafael Kramann, Daniel J. Rader, Peter Libby, Sasha A. Singh, Elena Aikawa
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M Haarhaus, V Brandenburg, K Kalantar-Zadeh, P Stenvinkel, P Magnusson |
Nature Reviews Nephrology | 2017 |
Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus
TJ Oh, CH Ahn, BR Kim, KM Kim, JH Moon, S Lim, KS Park, C Lim, HC Jang, SH Choi |
Cardiovascular Diabetology | 2017 |
Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in MenHighlights
C Goettsch, H Iwata, JD Hutcheson, CJ ODonnell, R Chapurlat, NR Cook, M Aikawa, P Szulc, E Aikawa |
Arteriosclerosis, thrombosis, and vascular biology | 2017 |
A Rock and a Hard Place: Chiseling Away at the Multiple Mechanisms of Aortic Stenosis
E Aikawa, P Libby |
Circulation | 2017 |
Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes
J Li, C Chen, Y Li, DJ Matye, Y Wang, WX Ding, T Li |
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2017 |
Giving Calcification Its Due: Recognition of a Diverse Disease: A First Attempt to Standardize the Field
JD Hutcheson, MC Blaser, E Aikawa |
Circulation research | 2017 |
In vitro 3D model and miRNA drug delivery to target calcific aortic valve disease
CF van der Ven, PJ Wu, MW Tibbitt, A Mil, JP Sluijter, R Langer, E Aikawa |
Clinical Science | 2017 |
Extracellular Vesicles as Protagonists of Diabetic Cardiovascular Pathology
D Gustafson, S Veitch, JE Fish |
Frontiers in Cardiovascular Medicine | 2017 |
Microvesicles in Atherosclerosis and Angiogenesis: From Bench to Bedside and Reverse
L Badimon, R Suades, G Arderiu, E Peña, G Chiva-Blanch, T Padró |
Frontiers in Cardiovascular Medicine | 2017 |
Extracellular Vesicles As Mediators of Cardiovascular Calcification
AB Nik, JD Hutcheson, E Aikawa |
Frontiers in Cardiovascular Medicine | 2017 |
Endothelial- and Immune Cell-Derived Extracellular Vesicles in the Regulation of Cardiovascular Health and Disease
F Jansen, Q Li, A Pfeifer, N Werner |
JACC: Basic to Translational Science | 2017 |
Sortilin and Its Multiple Roles in Cardiovascular and Metabolic DiseasesHighlights
C Goettsch, M Kjolby, E Aikawa |
Arteriosclerosis, thrombosis, and vascular biology | 2017 |
Imaging Atherosclerotic Plaque Calcification: Translating Biology
G Bailey, J Meadows, AR Morrison |
Current Atherosclerosis Reports | 2016 |
A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification
C Goettsch, JD Hutcheson, S Hagita, MA Rogers, MD Creager, T Pham, J Choi, AK Mlynarchik, B Pieper, M Kjolby, M Aikawa, E Aikawa |
Atherosclerosis | 2016 |
Calcification in atherosclerotic lesions:
H Lu, M Sheppard, A Daugherty |
Current Opinion in Lipidology | 2016 |
Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β ProductionHighlights
N Ceneri, L Zhao, BD Young, A Healy, S Coskun, H Vasavada, TO Yarovinsky, K Ike, R Pardi, L Qin, L Qin, G Tellides, K Hirschi, J Meadows, R Soufer, HJ Chun, MM Sadeghi, JR Bender, AR Morrison |
Arteriosclerosis, thrombosis, and vascular biology | 2016 |