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Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells
- Source :
- Translational Research. 176:18-28.e2
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Atherosclerosis is a mechanobiology-related disease that preferentially develops in the aortic arch and arterial branches, which are exposed to disturbed/turbulent blood flow but less in thoracic aorta where the flow pattern is steady laminar flow (LF). Increasing evidence supports that steady LF with high shear stress is protective against atherosclerosis. However, the molecular mechanisms of LF-mediated atheroprotection remain incompletely understood. Hippo/YAP (yes-associated protein) pathway senses and effects mechanical cues and has been reported to be a master regulator of cell proliferation, differentiation, and tissue homeostasis. Here, we show that LF inhibits YAP activity in endothelial cells (ECs). We observed that YAP is highly expressed in mouse EC–enriched tissues (lung and aorta) and in human ECs. Furthermore, we found in apolipoprotein E deficient (ApoE -/- ) mice and human ECs, LF decreased the level of nuclear YAP protein and YAP target gene expression (connective tissue growth factor and cysteine-rich protein 61) through promoting Hippo kinases LATS1/2-dependent YAP (Serine 127) phosphorylation. Functionally, we revealed that YAP depletion in ECs phenocopying LF responses, reduced the expression of cell cycle gene cyclin A1 ( CCNA1 ) and proinflammatory gene CCL2 ( MCP-1 ). Taken together, we demonstrate that atheroprotective LF inhibits endothelial YAP activation, which may contribute to LF-mediated ECs quiescence and anti-inflammation.
- Subjects :
- Male
0301 basic medicine
medicine.medical_treatment
Aorta, Thoracic
Cell Cycle Proteins
Protein Serine-Threonine Kinases
030204 cardiovascular system & hematology
Biology
Article
03 medical and health sciences
0302 clinical medicine
Coronary Circulation
Physiology (medical)
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
Phosphorylation
Chemokine CCL2
Tissue homeostasis
Adaptor Proteins, Signal Transducing
Cell Nucleus
Hippo signaling pathway
Kinase
Tumor Suppressor Proteins
Growth factor
Biochemistry (medical)
Connective Tissue Growth Factor
Public Health, Environmental and Occupational Health
Endothelial Cells
YAP-Signaling Proteins
General Medicine
Atherosclerosis
Phosphoproteins
Mice, Inbred C57BL
CTGF
Protein Transport
030104 developmental biology
CYR61
Cancer research
Cyclin A1
Signal transduction
Cysteine-Rich Protein 61
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 19315244
- Volume :
- 176
- Database :
- OpenAIRE
- Journal :
- Translational Research
- Accession number :
- edsair.doi.dedup.....578b9b014b8d2b8a5850c58d2cee38a7