Mechanisms underlying unidirectional laminar shear stress-mediated Nrf2 activation in endothelial cells: Amplification of low shear stress signaling by primary cilia

Ishii, Tetsuro; Warabi, Eiji; Mann, Giovanni E.

doi:10.1016/j.redox.2021.102103

Cited by 15 publications

(10 citation statements)

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“…It keeps up the low-grade vascular inflammation and promotes the development of endothelial dysfunction and atherosclerosis. Recently, the primary cilia on ECs were suggested to amplify low unidirectional SS signaling, resulting in the activation of NRF2 and the protection of ECs from oxidative damage [6]. We discuss the data suggesting that, under inflammatory conditions, the lipid bilayer and the NMMII-generated tension could dampen high laminar SS.…”

Section: Forces and Plasma Membrane Mechanosensorsmentioning

confidence: 93%

“…Depending on the patterns of fluid SS acting on ECs, either anti-or pro-inflammatory mechanisms can be triggered in ECs. High laminar SS induces an anti-inflammatory response [2,5,6], while low laminar SS and disturbed patterns of SS, on the other hand, activate pro-inflammatory mechanisms in ECs [2,3]. The key transcription factors responsible for the low flow-induced inflammatory response of ECs are activator protein 1 (AP-1), nuclear factor κB (NF-κB) [3], and yesassociated protein/transcriptional coactivators with a PDZ-binding motif (YAP/TAZ) [7].…”

Section: Introduction 1blood Flow Patterns and The Pro-inflammatory R...mentioning

confidence: 99%

“…The key transcription factors responsible for the low flow-induced inflammatory response of ECs are activator protein 1 (AP-1), nuclear factor κB (NF-κB) [3], and yesassociated protein/transcriptional coactivators with a PDZ-binding motif (YAP/TAZ) [7]. The transcription factors Krüppel-like factor 2 (KLF2), myocyte enhancer factor 2 (MEF2) and nuclear factor erythroid 2-related factor 2 (NRF2) are known to activate an antiinflammatory response [3,6].…”

Section: Introduction 1blood Flow Patterns and The Pro-inflammatory R...mentioning

confidence: 99%

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Endothelial Cell Plasma Membrane Biomechanics Mediates Effects of Pro-Inflammatory Factors on Endothelial Mechanosensors: Vicious Circle Formation in Atherogenic Inflammation

Barvitenko¹,

Ashrafuzzaman

Lawen

et al. 2022

Membranes

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Chronic low-grade vascular inflammation and endothelial dysfunction significantly contribute to the pathogenesis of cardiovascular diseases. In endothelial cells (ECs), anti-inflammatory or pro-inflammatory signaling can be induced by different patterns of the fluid shear stress (SS) exerted by blood flow on ECs. Laminar blood flow with high magnitude is anti-inflammatory, while disturbed flow and laminar flow with low magnitude is pro-inflammatory. Endothelial mechanosensors are the key upstream signaling proteins in SS-induced pro- and anti-inflammatory responses. Being transmembrane proteins, mechanosensors, not only experience fluid SS but also become regulated by the biomechanical properties of the lipid bilayer and the cytoskeleton. We review the apparent effects of pro-inflammatory factors (hypoxia, oxidative stress, hypercholesterolemia, and cytokines) on the biomechanics of the lipid bilayer and the cytoskeleton. An analysis of the available data suggests that the formation of a vicious circle may occur, in which pro-inflammatory cytokines enhance and attenuate SS-induced pro-inflammatory and anti-inflammatory signaling, respectively.

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Section: Forces and Plasma Membrane Mechanosensorsmentioning

confidence: 93%

Section: Introduction 1blood Flow Patterns and The Pro-inflammatory R...mentioning

confidence: 99%

Section: Introduction 1blood Flow Patterns and The Pro-inflammatory R...mentioning

confidence: 99%

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Endothelial Cell Plasma Membrane Biomechanics Mediates Effects of Pro-Inflammatory Factors on Endothelial Mechanosensors: Vicious Circle Formation in Atherogenic Inflammation

Barvitenko¹,

Ashrafuzzaman

Lawen

et al. 2022

Membranes

View full text Add to dashboard Cite

show abstract

“…For example, NF-κB (nuclear factor-κB), AP-1 (activator protein 1), YAP/TAZ (yes-associated protein/transcriptional co-activator with PDZ-binding motif), HIF-1α (hypoxia-inducible factor 1α), KLF2/4 (krüppel-like factor) and Nrf2 (nuclear factor-E2-related factor 2) can perceive extracellular signals such as oxygen levels and inflammatory cues, as they convert mechanical forces from the blood flow to cytoplasm. Specifically, when ECs are exposed to laminar shear stress, Nrf2 can protect ECs from oxidative stress by upregulating the expression of detoxifying enzymes, antioxidant enzymes, and proteins ( Mann and Forman, 2015 ; Ishii et al, 2021 ). KLF2 is another important mediator of endothelial anti-inflammatory and anti-thrombotic properties ( Boon and Horrevoets, 2009 ; Marin et al, 2013 ).…”

Section: Flow Patterns Fluid Shear Stress and Endothelial Cellsmentioning

confidence: 99%

“…Frontiers in Cell and Developmental Biology frontiersin.org mechanical forces from the blood flow to cytoplasm. Specifically, when ECs are exposed to laminar shear stress, Nrf2 can protect ECs from oxidative stress by upregulating the expression of detoxifying enzymes, antioxidant enzymes, and proteins (Mann and Forman, 2015;Ishii et al, 2021). KLF2 is another important mediator of endothelial anti-inflammatory and anti-thrombotic properties (Boon and Horrevoets, 2009;Marin et al, 2013).…”

Section: Goligorsky (2022) 2021mentioning

confidence: 99%

Role of blood flow in endothelial functionality: a review

Zhou,

Jiang,

Ventikos

2023

Front. Cell Dev. Biol.

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Endothelial cells, located on the surface of blood vessel walls, are constantly stimulated by mechanical forces from the blood flow. The mechanical forces, i.e., fluid shear stress, induced by the blood flow play a pivotal role in controlling multiple physiological processes at the endothelium and in regulating various pathways that maintain homeostasis and vascular function. In this review, research looking at different blood fluid patterns and fluid shear stress in the circulation system is summarized, together with the interactions between the blood flow and the endothelial cells. This review also highlights the flow profile as a response to the configurational changes of the endothelial glycocalyx, which is less revisited in previous reviews. The role of endothelial glycocalyx in maintaining endothelium health and the strategies for the restoration of damaged endothelial glycocalyx are discussed from the perspective of the fluid shear stress. This review provides a new perspective regarding our understanding of the role that blood flow plays in regulating endothelial functionality.

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Venous thrombosis and obesity: from clinical needs to therapeutic challenges

La Rosa,

Montecucco,

Liberale

et al. 2024

Intern Emerg Med

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Weight bias and stigma have limited the awareness of the systemic consequences related to obesity. As the narrative evolves, obesity is emerging as a driver and enhancer of many pathological conditions. Among these, the risk of venous thromboembolism (VTE) is a critical concern linked to obesity, ranking as the third most common cardiovascular condition. Obesity is recognized as a multifactorial risk factor for VTE, influenced by genetic, demographic, behavioral, and socio-economic conditions. Despite established links, the exact incidence of obesity related VTE in the general population remains largely unknown. The complexity of distinguishing between provoked and unprovoked VTE, coupled with gaps in obesity definition and assessment still complicates a tailored risk assessment of VTE risk. Obesity reactivity, hypercoagulability, and endothelial dysfunction are driven by the so-called ‘adiposopathy’. This state of chronic inflammation and metabolic disturbance amplifies thrombin generation and alters endothelial function, promoting a pro-thrombotic environment. Additionally, the inflammation-induced clot formation—also referred to as ‘immunothrombosis’ further exacerbates VTE risk in people living with obesity. Furthermore, current evidence highlights significant gaps in the management of obesity related VTE, particularly concerning prophylaxis and treatment efficacy of anticoagulants in people living with obesity. This review underscores the need for tailored therapeutic approaches and well-designed clinical trials to address the unique challenges posed by obesity in VTE prevention and management. Advanced research and innovative strategies are imperative to improve outcomes and reduce the burden of VTE in people living with obesity.

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Mechanisms underlying unidirectional laminar shear stress-mediated Nrf2 activation in endothelial cells: Amplification of low shear stress signaling by primary cilia

Cited by 15 publications

References 315 publications

Endothelial Cell Plasma Membrane Biomechanics Mediates Effects of Pro-Inflammatory Factors on Endothelial Mechanosensors: Vicious Circle Formation in Atherogenic Inflammation

Endothelial Cell Plasma Membrane Biomechanics Mediates Effects of Pro-Inflammatory Factors on Endothelial Mechanosensors: Vicious Circle Formation in Atherogenic Inflammation

Role of blood flow in endothelial functionality: a review

Venous thrombosis and obesity: from clinical needs to therapeutic challenges

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