Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

Goettsch, Claudia; Hutcheson, Joshua D.; Aikawa, Masanori; Iwata, Hiroshi; Pham, Tan; Nykjaer, Anders; Kjølby, Mads; Rogers, Maximillian A.; Michel, Thomas; Shibasaki, Manabu; Hagita, Sumihiko; Kramann, Rafael; Rader, Daniel J.; Libby, Peter; Singh, Sasha A; Aikawa, Elena

doi:10.1172/jci80851

Cited by 213 publications

(253 citation statements)

References 51 publications

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“…Recently, we and others have identified a putative Sort1 phosphorylation site serine-825 (S825) via proteomics approaches (24, 28, 29). S825 is located on the cytoplasmic tail of Sort1 immediately adjacent to a conserved DXXLL motif (S 825 DEDLL in Sort1) that mediates Sort1 interaction with the trafficking adaptor Golgi–associated, γ-adaptin ear–containing, ARF-binding protein-2 (GGA2) (28, 30, 31).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Li¹,

Cheng²,

Li³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Sortilin 1(Sort1) is a vesicle trafficking receptor that mediates protein sorting in the endocytic and exocytic pathways. Sort1 is a component of the GLUT4 storage vesicles in adipocytes and is also involved in the regulation of adipogenesis. Sort1 protein is reduced in adipose of obese mice and humans, but the underlying cause is not fully understood. Here we report that insulin/PI3K/AKT signaling cascade critically regulates adipose Sort1 protein abundance. Administration of a PI3K inhibitor rapidly decreased Sort1 protein but not mRNA in adipose of chow-fed mice. In 3T3-L1 adipocytes, serum-starvation or inhibition of the PI3K/AKT signaling also decreased Sort1 protein without affecting Sort1 mRNA expression. Sort1 protein downregulation upon PI3K inhibition was blocked by pretreatment of MG132 but not Bafilomycin A1, suggesting that PI3K inhibition caused Sort1 degradation via the proteasome pathway. Using a phospho-specific Sort1 antibody, we showed that endogenous Sort1 was phosphorylated at S825 adjacent to the DXXLL sorting motif on the cytoplasmic tail. We demonstrated that mutagenesis that abolished Sort1 S825 phosphorylation decreased insulin-stimulated Sort1 localization on the plasma membrane and Sort1 protein stability in 3T3-L1 adipocytes. However, endogenous Sort1 phosphorylation at S825 was not affected by insulin stimulation or by inhibition of PI3K. In conclusion, this study revealed an important role of insulin signaling in regulating adipose Sort1 protein stability, and further suggests that impaired insulin signaling may underlie reduced adipose Sort1 in obesity. The cellular events downstream of insulin/PI3K/AKT signaling that mediates insulin regulation of Sort1 stability requires further investigation.

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Section: Resultsmentioning

confidence: 99%

Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Li¹,

Cheng²,

Li³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…This approach is rapid and efficient and mimics the Ldlr-deficient condition, augmenting atherosclerosis within a short period in C57BL/6 mice. [150][151][152]154 However, the C57BL/6 mouse strain, but not other normolipidemic mouse strains such as FVB, 129, and BALB/C, responds to enhanced expression of PCSK9 activity. 151,152 There is also evidence that PCSK9 has effects independent of LDL receptor regulation.…”

Section: Viral-based Expression Systemsmentioning

confidence: 99%

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

Daugherty¹,

Tall²,

Daemen³

et al. 2017

ATVB

293

215

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Abstract-Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions. (Arterioscler Thromb Vasc Biol. 2017;37:e131-e157.

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“…Similar to its function in vascular SMCs, Annexin VI mediates calcium binding in EVs, promoting mineral formation. Conditions that simulate inflammation-induced osteogenic changes in SMCs result in the loading of active tissue non-specific alkaline phosphatase (TNAP) into EVs through intracellular trafficking mechanisms directed by the sorting receptor sortilin [22*]. Active TNAP hydrolyzes the calcification inhibitor pyrophosphate and produces free phosphate required for mineralization, promoting mineralization even in normal ranges of extracellular phosphate.…”

Section: Extracellular Vesicles As Mediators Of Cell-matrix Interactionsmentioning

confidence: 99%

Extracellular vesicles in cardiovascular homeostasis and disease

Hutcheson

Aikawa

2018

Current Opinion in Cardiology

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Purpose of review Extracellular vesicles (EVs) have emerged as one of the most important means through which cells interact with each other and the extracellular environment, but EV research remains challenging due to their small size and limited amount of material required for traditional molecular biology assays. The advent of new technologies and standards in the field, however, have led to increased mechanistic insight into EV function. Herein, the latest studies on the role of EVs in cardiovascular physiology and pathology are discussed. Recent findings EVs help control cardiovascular homeostasis and remodeling by mediating communication between cells and directing alterations in the extracellular matrix to respond to changes in the environment. The message carried from the parent cell to extracellular space can be intended for both local (within the same tissue) and distal (downstream of blood flow) targets. Pathological cargo loaded within EVs could further result in various diseases. On the other hand, new studies indicate that injection of EVs obtained from cultured cells into diseased tissues can promote restoration of normal tissue function. Summary EVs are an integral part of cell and tissue function, and harnessing the properties inherent to EVs may provide a therapeutic strategy to promote tissue regeneration.

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Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

Cited by 213 publications

References 51 publications

Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

Extracellular vesicles in cardiovascular homeostasis and disease

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