Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells.
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.
Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Suowen
S
Xu
Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Marina
M
Koroleva
Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Meimei
M
Yin
Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY. Electronic address: Zheng-gen_Jin@urmc.rochester.edu.
Zheng Gen
ZG
Jin
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D003326:Coronary Circulation; D056750:Cyclin A1 / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C501848:CCN1 protein, human; C526317:CCN2 protein, human; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D056750:Cyclin A1; D055515:Cysteine-Rich Protein 61; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D055513:Connective Tissue Growth Factor; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases