Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis.
The focal nature of atherosclerotic lesions suggests an important role of local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechanotransduction and vascular homeostasis. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of atheroprone endothelial phenotypes and the consequential development of atherosclerotic lesions. We found that exposure of cultured endothelial cells (ECs) to the atheroprone disturbed flow resulted in YAP/TAZ activation and translocation into EC nucleus to up-regulate the target genes, including cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). In contrast, the athero-protective laminar flow suppressed YAP/TAZ activities. En face analysis of mouse arteries demonstrated an increased nuclear localization of YAP/TAZ and elevated levels of the target genes in the endothelium in atheroprone areas compared with athero-protective areas. YAP/TAZ knockdown significantly attenuated the disturbed flow induction of EC proliferative and proinflammatory phenotypes, whereas overexpression of constitutively active YAP was sufficient to promote EC proliferation and inflammation. In addition, treatment with statin, an antiatherosclerotic drug, inhibited YAP/TAZ activities to diminish the disturbed flow-induced proliferation and inflammation. In vivo blockade of YAP/TAZ translation by morpholino oligos significantly reduced endothelial inflammation and the size of atherosclerotic lesions. Our results demonstrate a critical role of the activation of YAP/TAZ by disturbed flow in promoting atheroprone phenotypes and atherosclerotic lesion development. Therefore, inhibition of YAP/TAZ activation is a promising athero-protective therapeutic strategy.
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Kuei-Chun
KC
Wang
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Yi-Ting
YT
Yeh
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Phu
P
Nguyen
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Elaine
E
Limqueco
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Jocelyn
J
Lopez
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Satenick
S
Thorossian
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
Kun-Liang
KL
Guan
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; shuchien@ucsd.edu yili@ucsd.edu.
Yi-Shuan J
YJ
Li
Institute of Engineering in Medicine and Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; shuchien@ucsd.edu yili@ucsd.edu.
Shu
S
Chien
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017536:Carotid Artery, Common / Q000473:pathology; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D012212:Rheology; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
C491304:ANKRD1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor
atherogenesis; disturbed flow; endothelial cells; mechanotransduction
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