Targeting Mechanosensitive Transcription Factors in Atherosclerosis

Niu, Niu; Xu, Suowen; Yang, Xu; Little, Peter J.; Jin, Zhigang

doi:10.1016/j.tips.2019.02.004

Cited by 131 publications

(111 citation statements)

References 107 publications

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“…KLF2 is widely regarded as a key mechanosensitive transcription factor involved in vascular protection against atherosclerosis and has been suggested as a valuable treatment target for preventing endothelial inflammation induced by disturbed blood flow and OSS . Although there have been some studies investigating the effects of GPRs in cardiovascular disease, there has been little to no research on the effects of GPR agonism on KLF2 expression.…”

Section: Discussionmentioning

confidence: 99%

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

et al. 2019

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Atherosclerosis is a common and deadly cardiovascular disease with extremely high prevalence. Areas of the vasculature exposed to oscillatory shear stress (OSS) or disturbed blood flow are particularly prone to the development of atherosclerotic lesions. In part, various mechanosensitive receptors on the surface of endothelial cells play a role in regulating the ability of the vasculature to cope with variations in blood flow patterns. However, the exact mechanisms behind flow-mediated endothelial responses remain poorly understood. Along with the development of highly specific receptor agonists, the class of G coupled-protein receptors has been receiving increasing attention as potential therapeutic targets. G coupled-protein receptor 81 (GPR81), also known as hydroxycarboxylic acid receptor 1 (HCA 1 ), is activated by lactate, its endogenous ligand. In the present study, we show for the first time that expression of GPR81 is significantly downregulated in response to OSS in endothelial cells and that activation of GPR81 using physiologically relevant doses of lactate can rescue OSS-induced reduced GPR81 expression. Importantly, our findings demonstrate that activation of GPR81 can exert valuable atheroprotective effects in endothelial cells exposed to OSS by reducing oxidative stress and significantly downregulating the expression of inflammatory cytokines including interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and high mobility group box 1 (HMGB1). We also show that activation of GPR81 can potentially prevent the attachment of monocytes to the endothelium by suppressing OSS-induced secretion of vascular cellular adhesion molecule (VCAM)-1 and endothelial-selectin (E-selectin). Finally, we show that activation of GPR81 can rescue OSS-induced reduced expression of the key atheroprotective transcription factor Kruppel-like factor 2 (KLF2), which is mediated through the extracellularregulated kinase 5 (ERK5) pathway. These findings demonstrate a potential Abbreviations: ECL, electrochemiluminescence; E-selectin, endothelial-selectin; ELISA, Enzyme-linked immunosorbent assay; ERK5, extracellularregulated kinase 5; FBS, fetal bovine serum; GPR81, G coupled-protein receptor 81; GPCRs, G protein-coupled receptors; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMGB1, high mobility group box 1; HSS, high shear stress; HUVECs, human umbilical vascular endothelial cells; HCA 1 , hydroxycarboxylic acid receptor 1; IL-6, interleukin; KLF2, Kruppel-like factor 2; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein; OSS, oscillatory shear stress; PAK1, p21-activated kinase 1; PVDF, polyvinylidene fluoride; ROS, reactive oxygen species; RT-PCR, reverse transcription PCR; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; VCAM-1, vascular cellular adhesion molecule.

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Section: Discussionmentioning

confidence: 99%

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

et al. 2019

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“…Shear stress plays crucial roles in the maintenance and disturbance of vascular homeostasis, and different flows greatly modify endothelial phenotypes and determine the uneven distribution of atherosclerotic lesions 3 . In straight sections of the arterial tree, steady unidirectional laminar flow (UF) induces endothelial protective effects, such as anti-oxidation, antiinflammation, and anti-atherogenesis; while in branches and curved sections, disturbed flow (DF) evokes proatherogenic responses, such as oxidative stress, inflammation, and atherogenesis 4 . Local flow around the atherosclerotic micro-environment defines the endothelial phenotype, which leads to the initiation and development of plaques 5 .…”

Section: Introductionmentioning

confidence: 99%

“…DF and UF modulate different aspects of ECs via mechanosensitive transcription factors, such as KLF2/4, HIF-1α, YAP/TAZ/TEAD, NF-κB, NRF2, and AP-1 4 . Accumulating studies have indicated that YAP/TAZ/ TEAD signaling represents a promising therapeutic target for the prevention and treatment of atherosclerosis 4 .…”

Section: Introductionmentioning

confidence: 99%

Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

Yuan

et al. 2020

Cell Death Dis

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Atherosclerosis is a multifactorial disease of the vasculature, and shear stress is a crucial regulator of its process. Disturbed flow promotes atherosclerotic effects, while laminar flow has a protective action on the endothelium. Hippo/YAP is a major cascade that senses various mechanical cues and mediates the expression of pro-inflammatory genes. However, the mechanism modulating the transcription factor YAP in response to different patterns of blood flow remains unclear. In this study, we provide evidence that shear stress modulates YAP activity via autophagy in endothelial cells. Laminar flow promoted the expression of the autophagic markers BECLIN 1 and LC3II/LC3I. Autophagy blockade using a chemical inhibitor repressed YAP degradation under laminar flow. Conversely, the induction of autophagy under disturbed flow partially antagonized the nuclear import and transcriptional activation of YAP. In parallel, laminar flow led to the increased expression of SIRT1 protein, a NAD +-dependent deacetylase. Further investigation showed that SIRT1-mediated YAP deacetylation. The forced expression of SIRT1 under disturbed flow effectively attenuated YAP activation and nuclear accumulation, thereby downregulating the expression of proinflammatory genes. In atheroprone vessels of mice receiving rapamycin to induce autophagy, the enhanced expression of SIRT1 was observed together with YAP repression. Altogether, these results show that endothelial autophagy and SIRT1 expression induced by laminar flow contribute to the inhibition of Hippo/YAP signaling and interrupt atherosclerotic plaque formation.

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“…In this review, we will first discuss the structural and signaling factors that affect YAP nuclear transport and then describe the mechanisms of YAP translocation in terms of mechanical signaling, protein modification, and metabolism. The aim of this review is to demonstrate how YAP nuclear import and export affect its function, and identify potential new targets for treating hepatocellular carcinoma, gastric cancer, atherosclerosis, and angiogenesis (Wang et al, 2017; Li et al, 2019; Niu et al, 2019; Yan et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

Zou

Feng

et al. 2020

Cell Biology International

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Nuclear‐cytoplasmic transport is necessary for the biological function of nuclear proteins. The mechanism underlying this process is very complex and has been a subject of intense research. Yes‐associated protein (YAP), a Hippo signaling pathway effector, localizes to both the cytoplasm and the nucleus and can influence cell proliferation, stem cell status, and tissue homeostasis. Recent studies have focused on the significance of YAP distribution between the nucleus and the cytoplasm in disease, but it remains unclear how this dynamic process is regulated. In this review, we discuss YAP nuclear‐cytoplasmic transport under different physiological and pathological conditions in terms of mechanical signaling, protein modification, and metabolism. Understanding the mechanisms underlying nuclear‐cytoplasmic YAP transport mechanism under different physiological and pathological conditions may help identify important targets for disease treatment.

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Targeting Mechanosensitive Transcription Factors in Atherosclerosis

Cited by 131 publications

References 107 publications

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

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