Silencing KRIT1 Partially Reverses the Effects of Disturbed Flow on the Endothelial Cell Transcriptome

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(9), С. 4340 - 4340

Опубликована: Май 2, 2025

Endothelial cells respond to forces generated by laminar blood flow with changes in vasodilation, anticoagulant, fibrinolytic, or anti-inflammatory functions which preserve vessel patency. These responses shear stress are primarily mediated the modulation of following transcription factors: Krüppel-like factors 2 and 4 (KLF2 KLF4). Notably, disturbed patterns, found vascular areas predisposed atherosclerosis, significantly reduce endothelial expression KLF2 KLF4, resulting transcriptome that exacerbate inflammation thrombosis. The CCM (Cerebral Cavernous Malformation) complex, comprising KRIT1 (Krev1 interaction trapped gene 1), CCM2 (Malcavernin), CCM3 (Programmed cell death protein 10), suppresses KLF4. Loss function complex has recently been suggested protect from coronary atherosclerosis humans. We thus hypothesized silencing KRIT1, central scaffold can normalize atherogenic effects on human transcriptome. Bulk RNA sequencing (RNA-seq) was conducted umbilical vein (HUVECs) after silenced using specific small interfering (siRNA). were exposed three different conditions for 24 h, as follows: pulsatile (laminar flow), oscillatory (disturbed static (no flow). HUVECs restored KLF4 under stress. This treatment resulted a transcriptomic profile similar findings suggest inhibition endothelium plays vasoprotective role reactivating protective program help resist flow. Targeting genes activate well-known programs enhance resilience inflammation, hypoxia, angiogenesis conditions, providing novel pathway preventing atherothrombosis.

Язык: Английский

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Endothelial Cu Uptake Transporter CTR1 Senses Disturbed Flow to Promote Atherosclerosis through Cuproptosis

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

ABSTRACT Endothelial cells (ECs) lining blood vessels sense disturbed flow (D-flow), which drives mitochondrial dysfunction and atherosclerosis. Copper (Cu) is an essential micronutrient, its disruption of homeostasis has been implicated in Cellular Cu levels are tightly controlled by transport proteins including the importer CTR1. Cuproptosis a recently discovered form regulated cell death triggered accumulation, but endogenous stimulants role atherosclerosis remain unknown. Using EC-specific CTR1-deficient mice cultured ECs, we show that endothelial CTR1 responds to D-flow increasing through interaction with transporter SLC25A3 at caveolae/lipid rafts. This leads aggregation lipoylated proteins, dysfunction, cuproptosis, thereby exacerbating Importantly, mitochondria-targeted Cu-chelating nanoparticles effectively mitigate D-flow-induced cuproptosis atherosclerosis, highlighting CTR1-SLC25A3-mitochondrial axis as potential therapeutic target.

Язык: Английский

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The Essential Role of Sphingolipids in TRPC5 Ion Channel Localization and Functionality within Lipid Rafts

Pharmacological Research, Год журнала: 2025, Номер unknown, С. 107648 - 107648

Опубликована: Фев. 1, 2025

Язык: Английский

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Silencing KRIT1 Partially Reverses the Effects of Disturbed Flow on The Endothelial Cell Transcriptome

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 14, 2025

Endothelial cells respond to forces generated by laminar blood flow with changes in vasodilation, anticoagulant, fibrinolytic, or anti-inflammatory functions which preserve vessel patency. These responses sheer stress are primarily mediated the modulation of transcription factors Krüppel-like 2 and 4 (KLF2 KLF4). Notably, disturbed patterns, found vascular areas predisposed atherosclerosis, significantly reduce endothelial expression KLF2 KLF4, resulting transcriptome that exacerbate inflammation thrombosis. The CCM complex, comprising KRIT1, CCM2, CCM3, suppresses KLF4. Loss function complex has recently been suggested protect from coronary atherosclerosis humans. We thus hypothesized silencing KRIT1 , central scaffold can normalize atherogenic effects on human transcriptome. Bulk RNA sequencing (RNA-seq) was conducted umbilical vein (HUVECs) after silenced using specific siRNAs. were exposed three different conditions for 24 hours: pulsatile shear (laminar flow), oscillatory (disturbed static (no flow). HUVECs restored KLF4 under stress. This treatment resulted a transcriptomic profile similar findings suggest inhibition endothelium plays vasoprotective role reactivating protective gene program help resist flow. Targeting genes activate well-known programs enhance resilience inflammation, hypoxia, angiogenesis conditions, providing novel pathway preventing atherosclerosis. expressing such as Krüppel-Like Factors Under (OS) characterized flow, suppressed cells, is linked an atheroprone includes increased risk (unhealthy endothelium). Our work shows OS increases mRNA levels well associated angiogenesis, those observed (healthy

Язык: Английский

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TRPV4 in cerebral small vessel disease: A key interacting partner

Vascular Pharmacology, Год журнала: 2025, Номер unknown, С. 107492 - 107492

Опубликована: Март 1, 2025

Cerebral small vessel disease (cSVD) is a major cause of vascular cognitive impairment and dementia. The underlying mechanisms are centered around the dysfunction neurovascular unit include an blood-brain barrier (BBB) permeability, decreased cerebrovascular reactivity cerebral hypoperfusion. cells composing express wide variety mechanosensitive ion channels that relevant for these processes. Recent research has increasingly focused on mechanobiology microvessels with recent evidence pointing towards significant role transient receptor potential vanilloid 4 (TRPV4). This Ca2+-permeable channel regulates key physiological functions, including tone, angiogenesis, BBB integrity neuroinflammation. Beyond its role, implicates TRPV4 in pathological processes such as remodelling, impaired reactivity, dysfunction. In this review, we explore multiple roles within unit, interactions molecular partners, discuss contribution to cSVD.

Язык: Английский

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Ammonium tetrathiomolybdate attenuates acetaminophen-induced acute liver failure by inhibiting the TRPV4/Calcium/NF-κB signaling pathway

Biochemical Pharmacology, Год журнала: 2025, Номер unknown, С. 116917 - 116917

Опубликована: Апрель 1, 2025

Язык: Английский

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Optical Tweezer-Driven Mechanotransduction: Probing pN-Scale Forces and Calcium-Mediated Redox Signaling in Single Endothelial Cells

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Апрель 15, 2025

Endothelial cells (ECs) regulate vascular function by converting mechanical forces into biochemical signals; however, the molecular mechanisms of pN-scale mechanotransduction remain elusive. Here, we develop an optical tweezer-integrated confocal microscopy system that allows precise, noninvasive manipulation cell membrane localization with stimuli within 0-100 pN range while monitoring Ca2+-mediated NO/ROS redox signaling in situ single ECs under varying force parameters. We show stimulation regulates extracellular Ca2+ influx, triggering downstream production NO and ROS, which subsequently affects intracellular homeostasis. Key mechanosensitive ion channels (e.g., Piezo1 TRPV4) cytoskeletal components F-actin) facilitate force-induced signaling. further delineate roles tension-dominant versus hybrid tension-tether models mechanotransduction, revealing their differential engagement transmission pathways. This mechanistic framework establishes direct connections between input characteristics redox-regulated

Язык: Английский

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Smooth muscle Cxcl12 contributions to vascular remodeling in flow and hypoxia-induced pulmonary hypertension

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 110207 - 110207

Опубликована: Май 1, 2025

Patients with congenital heart disease (CHD) causing significant left-to-right shunting of blood are at risk developing pulmonary arterial hypertension (PAH). However, the underlying mechanism by which overcirculation and shear stress drive vascular remodeling remains poorly understood. Our study established a "two-hit" murine model severe (PH) combining left pneumonectomy (LP) chronic hypoxia (LP/Hx). Using transgenic reporter lines, immunofluorescence (IF) staining, advanced microscopy, we conducted cell-lineage tracing for cells, including smooth muscle cells (SMCs), endothelial (ECs), pericytes. findings reveal that SMCs key contributors to distal arteriolar following LP LP/Hx. PCR analysis isolated from LP/Hx animals demonstrated upregulation markers associated contractility, proliferation, Cxcl12 expression. Consistently, CXCL12 was found be overexpressed in SMC layer vessels patients PAH-CHD. Lastly, vitro experiments healthy human artery showed laminar induces upregulation. These provide novel insights into role flow-induced their mechanosensitive response stress. This PH is valuable tool future research targeted therapeutics PAH.

Язык: Английский

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RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection

Cell Death and Differentiation, Год журнала: 2025, Номер unknown

Опубликована: Май 14, 2025

Язык: Английский

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TRPV4—A Multifunctional Cellular Sensor Protein with Therapeutic Potential

Sensors, Год журнала: 2024, Номер 24(21), С. 6923 - 6923

Опубликована: Окт. 29, 2024

Transient receptor potential vanilloid (TRPV) channel proteins belong to the superfamily of TRP that form cationic channels in animal cell membranes. These have various subtype-specific functions, serving, for example, as sensors pain, pressure, pH, and mechanical extracellular stimuli. The sensing cues by TRPV4 triggers Ca2+-influx through channel, subsequently coordinating numerous intracellular signaling cascades a spatio-temporal manner. As TRPV play such wide role cellular physiological loss or impaired protein activity naturally contributes many pathophysiological processes. This review concentrates on known functions sensor their therapeutic target.

Язык: Английский

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