British Journal of Pharmacology最新文献

{"title":"Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1^G93A amyotrophic lateral sclerosis (ALS) mice.","authors":"Laura Moreno-Martinez, Núria Gaja-Capdevila, Laura Mosqueira-Martín, Mireia Herrando-Grabulosa, Laura Rodriguez-Gomez, Klaudia Gonzalez-Imaz, Ana C Calvo, Maialen Sagartzazu-Aizpurua, Leticia Moreno-García, Jose Manuel Fuentes, Abraham Acevedo-Arozena, Jesús María Aizpurua, José Ignacio Miranda, Adolfo López de Munain, Ainara Vallejo-Illarramendi, Xavier Navarro, Rosario Osta, Francisco Javier Gil-Bea","doi":"10.1111/bph.17448","DOIUrl":"https://doi.org/10.1111/bph.17448","url":null,"abstract":"<p><strong>Background and purpose: </strong>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca²⁺ influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca²⁺, as a therapeutic target.</p><p><strong>Experimental approach: </strong>A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)^G93A mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.</p><p><strong>Key results: </strong>Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1^G93A mice produced preservation of motor nerve conduction, with the 61-mg·kg^-1 dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle.</p><p><strong>Conclusions and implications: </strong>FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vincamine ameliorates hepatic fibrosis via inhibiting S100A4-mediated farnesoid X receptor activation: based on liver microenvironment and enterohepatic circulation dependence.","authors":"Yu-Chen Jiang, Jia Guo, Sai-Hu Liu, Xu Dai, Chen-Yu Wang, Li-Hua Lian, Zhen-Yu Cui, Ji-Xing Nan, Yan-Ling Wu","doi":"10.1111/bph.17471","DOIUrl":"https://doi.org/10.1111/bph.17471","url":null,"abstract":"<p><strong>Background and purpose: </strong>Vincamine has extensive biological and pharmaceutical activity. We examined the hepatoprotective effects and mechanisms by which vincamine suppresses hepatic fibrosis.</p><p><strong>Experimental approach: </strong>Hepatic stellate cells (HSCs), TGF-β stimulated, were cultured with either vincamine, farnesoid X receptor (NR1H4; FXR) agonist or antagonist. Further, C57BL/6 mice were given thioacetamide (TAA) to induce hepatic fibrosis and subsequently treated with vincamine or curcumin.</p><p><strong>Key results: </strong>Vincamine regulated the deposition of extracellular matrix (ECM), inflammatory factors and S100A4, and up-regulated FXR and TGR5 (GPBA receptor) in activated HSCs, by activating FXR. FXR deficiency blocked vincamine effect on FXR, TGR5, α-smooth muscle actin (α-SMA) and IL1R1 in activated LX-2 cells. Vincamine corrected ECM imbalance, inflammatory secretion and FXR/TGR5 down-regulation in activated LX-2 cells with stimulating medium from LPS-primed THP-1 cells. S100A4 deficiency increased FXR and TGR5, and decreased IL-1β expression in activated THP-1. Further, S100A4 deficiency in activated macrophages could elevate FXR and TGR5 expression in activated LX-2, strengthening the impact of vincamine on α-SMA and IL-1β expression. Further, vincamine reduced serum ALT/AST levels, liver and intestinal histopathological changes, and caused ECM accumulation and protected the intestinal barrier in thioacetamide-induced hepatic fibrosis mice. Vincamine decreased inflammatory factors e.g. caspase 1 and IL-1β, and inhibited the S100A4-mediated FXR-TGR5 pathway.</p><p><strong>Conclusion and implications: </strong>Vincamine significantly reverses hepatic fibrosis via inhibiting S100A4 involved in the crosstalk between macrophages and HSCs, and by activating the FXR-TGR5 pathway. Targeting the S100A4-mediated FXR dependence on modulating the liver environment may be the key target of vincamine in inhibiting hepatic fibrosis.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An optimised Bcl-3 inhibitor for melanoma treatment.","authors":"Karunakar Saamarthy, Renée Daams, Wondossen Sime, Cecilia Persson, Eduard Chygorin, Kristofer Ahlqvist, Susan Evans-Axelsson, Daniel Strand, Ramin Massoumi","doi":"10.1111/bph.17467","DOIUrl":"https://doi.org/10.1111/bph.17467","url":null,"abstract":"<p><strong>Background and purpose: </strong>Malignant melanoma is the most lethal form of skin cancer, characterised by a poor survival rate. One of the key factors driving the aggressive growth of melanoma cells is the elevated expression of the proto-oncogene Bcl-3. This study aims to optimise, evaluate and characterise a second-generation Bcl-3 inhibitor, using melanoma as a model to demonstrate its potential therapeutic efficacy.</p><p><strong>Experimental approach: </strong>We synthesised and screened a series of structural analogues and selected A27, the most promising candidate for further investigation. We assessed whether A27 disrupted the interaction between Bcl-3 and its binding partner, p50, and examined the subsequent effects on cyclin D1 expression. Additionally, we evaluated the impact of A27 on melanoma cell proliferation and migration in vitro, as well as its therapeutic efficacy in various in vivo melanoma models.</p><p><strong>Key results: </strong>Nuclear magnetic resonance (NMR) confirmed that A27 directly binds to Bcl-3, effectively inhibiting its function. By disrupting the Bcl-3/p50 interaction, A27 led to a significant down-regulation of cyclin D1 expression. In cellular assays, A27 markedly reduced proliferation and migration of melanoma cells. In vivo, treatment with A27 resulted in a substantial reduction in melanoma tumour growth, with no observed toxicity in treated animals.</p><p><strong>Conclusions and implications: </strong>At present, no other Bcl-3 inhibitors exist for clinical application in the field of oncology, and as a result, our novel findings provide a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clinical need.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting FDX1 by trilobatin to inhibit cuproptosis in doxorubicin-induced cardiotoxicity.","authors":"Jiajia Wei, Guozhen Lan, Wenfang Zhang, Wang Ran, Yu Wei, Xin Liu, Yuandong Zhang, Qihai Gong, Haibo Li, Jianmei Gao","doi":"10.1111/bph.17468","DOIUrl":"https://doi.org/10.1111/bph.17468","url":null,"abstract":"<p><strong>Background and purpose: </strong>Doxorubicin (DOX), an anthracycline chemotherapeutic agent, whose use is limited owing to its dose-dependent cardiotoxicity. Mitochondrial oxidative stress plays a crucial role in the pathogenesis of DOX-induced cardiotoxicity (DIC). Trilobatin (TLB), a naturally occurring food additive, exhibits strong antioxidant properties, but its cardioprotective effects in DIC is unclear. This study investigates the cardioprotective effect of TLB on DIC.</p><p><strong>Experimental approach: </strong>DOX was used to generate an in vivo and in vitro model of cardiotoxicity. Echocardiography, enzyme-linked immunosorbent assay (ELISA) and haematoxylin and eosin (H&E) staining were used to evaluate the cardiac function in these models. To identify the targets of TLB, RNA-sequence analysis, molecular dynamics simulations, surface plasmon resonance binding assays and protein immunoblotting techniques were used. Transmission electron microscopy, along with dihydroethidium and Mito-SOX staining, was conducted to examine the impact of trilobatin on mitochondrial oxidative stress. SiRNA transfection was performed to confirm the role of ferredoxin 1 (FDX1) in DIC development.</p><p><strong>Key results: </strong>In DIC mice, TLB improved cardiac function in a dose-dependent manner and inhibited myocardial fibrosis in DIC mice. TLB also attenuated DOX-induced mitochondrial dysfunction and reduced cardiac mitochondrial oxidative stress. TLB was found to directly bind to FDX1 and suppresses cuproptosis after DOX treatment, causing significant inhibition of cuproptosis-related proteins.</p><p><strong>Conclusions and implications: </strong>This is the first study to show that TLB strongly inhibits DIC by reducing mitochondrial oxidative stress and controlling DOX-mediated cuproptosis by targeting FDX1. Therefore, TLB is as a potential phytochemical cardioprotective candidate for ameliorating DIC.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of the somatosensory-autonomic reflex and muscarinic receptors in exacerbation of allergic pulmonary inflammation by electroacupuncture.","authors":"Shuyan Liu, Jiayi Ge, Weili Liu, Zhidi Zhuang, Shenbin Liu","doi":"10.1111/bph.17415","DOIUrl":"https://doi.org/10.1111/bph.17415","url":null,"abstract":"<p><strong>Background and purpose: </strong>Emerging evidence suggests that electroacupuncture (EA) could cause autonomic reflexes to modulate visceral functions. However, the efficacy and underlying mechanisms for somatic stimulation on allergic pulmonary inflammation (API) remain elusive.</p><p><strong>Experimental approach: </strong>Mice were administered intranasal Papain to induce API. Distinct current (0,0.1, 0.2 and 0.5 mA) of EA at the back BL13, hindlimb ST36 and forelimb LU5 acupoint were then carried out. The control group underwent the same procedure but without current stimulation. Changes in API was assessed using immunohistochemistry, flow cytometry and haematoxylin and eosin (H&E) staining. Pharmacological approaches were used to investigate the underlying mechanisms of EA effects on API.</p><p><strong>Key results: </strong>EA at the back region but not limb regions, in a current intensity-dependent manner, exacerbated API, primarily causing a decrease in the survival rate and intensified inflammation in the lung, including the infiltration of lung type 2 innate lymphoid cells and eosinophils, and lung pathology scores. Blocking local thoracic sensory nerves with lidocaine or lung-innervated autonomic nerves with hexamethonium eliminates the EA-produced detrimental effects. Chemical pulmonary sympathectomy with 6-OHDA further enhanced lung pathology scores, but inhibiting the activity of pulmonary muscarinic receptors was sufficient to prevent the exacerbation of API induced by EA.</p><p><strong>Conclusion and implications: </strong>Our findings suggest that BL13 EA induces a somatic-autonomic reflex involving the pulmonary muscarinic receptors, thereby exacerbating API. The selective and intensity-dependency activation of body thoracic regions in driving pulmonary autonomic pathways could help optimise stimulation parameters, enhancing both efficacy and safety in modulating API.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of new small molecules for selective inhibition of SERCA 1 in patient-derived metastatic papillary thyroid cancer.","authors":"Seok-Mo Kim, Keunwan Park, Hyeok Jun Yun, Jung Min Kim, Kyung Hwa Choi, Ki Cheong Park","doi":"10.1111/bph.17442","DOIUrl":"https://doi.org/10.1111/bph.17442","url":null,"abstract":"<p><strong>Background and purpose: </strong>Papillary thyroid cancer (PTC) is a general thyroid cancer subtype; however, PTC is associated with metastasis or recurrence via anti-cancer drug resistance, rendering it practically incurable. Therefore, effective and reliable clinical approaches are urgently required.</p><p><strong>Experimental approach: </strong>We demonstrated the coordinated up-regulation of sarco/endoplasmic reticulum (ER) calcium ATPase 1 (SERCA1) in metastatic PTC under treatment with sorafenib or lenvatinib. We screened novel drug candidates in a patient-derived lymph node metastatic PTC and compared outcomes with those in non-metastatic and main mass PTC in an in vitro and in vivo model to propose a new clinical strategy.</p><p><strong>Key results: </strong>In the current study using patient-derived metastatic PTC cells, SERCA1 was considerably increased under sorafenib- or lenvatinib-treated conditions. SERCA is a critical component in cytosolic free calcium regulation and is regulated by calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) via NFκB. However, cardiac dysfunction was inevitable in vivo because of non-specific inhibition of SERCA isoforms by conventional SERCA inhibitors. This study designed a therapeutic approach with decreased cardiac dysfunction via SERCA1 isoform-specific inhibition by novel small molecules, CKP1 and CKP2, under severe ER stress conditions in patient-derived metastatic PTC. These novel SERCA1-specific inhibitors remarkably increased tumour shrinkage in the patient-derived metastatic PTC xenograft tumour model without cardiac dysfunction when used in combination with sorafenib or lenvatinib.</p><p><strong>Conclusion and implications: </strong>These outcomes suggest the potential efficacy of the novel combination strategy that uses targeted therapy to treat malignant cancer cells, such as sorafenib- or lenvatinib-resistant cancer cells.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"System level network data and models attack cancer drug resistance.","authors":"Márk Kerestély, Dávid Keresztes, Levente Szarka, Borbála M Kovács, Klára Schulc, Dániel V Veres, Peter Csermely","doi":"10.1111/bph.17469","DOIUrl":"https://doi.org/10.1111/bph.17469","url":null,"abstract":"<p><p>Drug resistance is responsible for >90% of cancer related deaths. Cancer drug resistance is a system level network phenomenon covering the entire cell. Small-scale interactomes and signalling network models of drug resistance guide directed drug development. Recently, proteome-wide human interactome and signalling network data have become available, which have been extended by drug-target interactions, drug resistance-inducing mutations, as well as by several cancer and drug resistance-related multi-omics datasets. System level signalling network models have become available examining therapy resistance, performing in silico clinical trials, and conducting large, in silico drug combination screens. Drug resistance network data and models have become interoperable and reliable. These advances paved the road for building proteome-wide drug resistance models.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing drug transporters in human primary muscle cells modulates atorvastatin pharmacokinetics: A pilot study.","authors":"Emilia Hoste, Louise Deldicque, Giulio G Muccioli, Nadtha Panin, Romano Terrasi, Adrien Paquot, Maxime Lingurski, Sébastien Pyr Dit Ruys, Vincent Haufroid, Laure Elens","doi":"10.1111/bph.17449","DOIUrl":"https://doi.org/10.1111/bph.17449","url":null,"abstract":"<p><strong>Background and purpose: </strong>Non-adherence to atorvastatin treatment is relatively common and partly due to statin-related myotoxicities (SRMs). The risk of developing SRM is dose- and concentration-dependent, highlighting the importance of atorvastatin pharmacokinetics. This study explored the inter-individual variabilities in expression of the atorvastatin transporter gene contributing to modulation of atorvastatin within the muscle cell.</p><p><strong>Experimental approach: </strong>mRNA levels of efflux and influx transporters were measured and modulated with siRNAs to evaluate effects on intracellular accumulation of atorvastatin in primary cultures of differentiated myotubes from 12 human volunteers.</p><p><strong>Key results: </strong>All genes assessed were expressed with a high inter-individual variability. In differentiated myotubes, efflux transporters were expressed at higher levels than the influx carriers. When considering efflux and influx transporters separately, ABCC1 and SLCO2B1 are the most highly expressed efflux and influx transporters. Suppression of ABCC1, ABCC4 and/or ABCG2 mRNA levels with siRNA significantly increased intracellular accumulation of atorvastatin in differentiated myotubes. Interestingly, the siRNA targeting ABCG2 had a moderate effect on intracellular accumulation of atorvastatin in a volunteer expressing the ABCG2 variant rs2231142 (c.421C>A, p.Gln141Lys). This hypothesis was further validated in a HEK recombinant model overexpressing ABCG2 either wild-type (421C) or variant (421A). Reduction of SLCO1B1 and SLCO2B1 mRNA levels significantly modified intracellular accumulation of atorvastatin in only some volunteers, depending on the expression levels of transporters.</p><p><strong>Conclusion and implications: </strong>Silencing ABCC1, ABCC4 or ABCG2 expression alters accumulation of atorvastatin in myotubes, whereas the effect of silencing influx transporters depends on the expression of these transporters.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Bruton tyrosine kinase (Btk) inhibition are steered by Bruton tyrosine kinase phylogeny.","authors":"Giorgio Minotti, Massimiliano Camilli, Emanuela Salvatorelli, Pierantonio Menna","doi":"10.1111/bph.17466","DOIUrl":"https://doi.org/10.1111/bph.17466","url":null,"abstract":"<p><p>Bruton tyrosine kinase (Btk) has long been known to play a key role in chronic lymphatic leukaemia, Waldenström macroglobulinaemia and other B-cell proliferative disorders. An impressive programme of drug discovery and clinical development led to the approval of covalent and non-covalent Btk inhibitors that became pillars of treatment of such malignancies. However, both a risk of cardiovascular events and the emergence of an elusive mutational landscape seem to complicate the clinical use of each Btk inhibitor. In this plain language mini-review, we show that the search for better Btk inhibitors is challenged by the ancestral origin of Btk, its homology with innocent kinases in cardiovascular system and unique phylogenetic-like modalities with which Btk can mutate upon exposure to one inhibitor or another. Whereas basic and clinical pharmacology is already at work to explore new avenues of Btk inhibition, phylogeny remains behind the curtain to steer achievements and failures in this field.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smooth muscle cell Piezo1 is essential for phenotypic switch and neointimal hyperplasia.","authors":"Fei-Ran Zhang, Jie Tang, Ying Lai, Shi-Qi Mo, Zhuo-Miao Lin, Qing-Qing Lei, Cong-Cong Han, An-Dong Zhou, Xiao-Fei Lv, Cheng Wang, Jing-Song Ou, Jia-Guo Zhou, Rui-Ping Pang","doi":"10.1111/bph.17436","DOIUrl":"https://doi.org/10.1111/bph.17436","url":null,"abstract":"<p><strong>Background and purpose: </strong>Disturbed blood flow is a critical factor in activation of vascular smooth muscle cells (VSMCs) and initiation of neointimal hyperplasia. The Piezo1 channel is a recent yet well-characterised mechanosensor that plays a vital role in vascular development and homeostasis. However, the role of VSMC Piezo1 in neointima development remains largely unknown. The purpose of this study is to investigate the functional role of Piezo1 channel in neointimal hyperplasia.</p><p><strong>Experimental approach: </strong>We measured the expression of Piezo1 in VSMC-rich neointima from human coronary artery samples and two mouse neointimal hyperplasia models which were induced by cast implantation or guidewire injury. We utilised VSMC-specific Piezo1 knockout mice to explore its function and the underlying mechanism of neointimal hyperplasia, both in vivo and in vitro.</p><p><strong>Key results: </strong>In human and mouse neointima samples, we observed a significant up-regulation of Piezo1 expression in the VSMC-rich neointima compared to the medial layer. VSMC-specific knockout of Piezo1 significantly reduced neointimal hyperplasia in both animal models. Activation of Piezo1 facilitates, whereas Piezo1 deficiency inhibits disturbed flow-induced cell proliferation, migration and synthetic phenotype switch. Mechanistic studies suggest that Piezo1 activates YAP and TAZ through Ca²⁺ and its downstream effectors calmodulin kinase II and calcineurin, which in turn drive VSMC proliferation and migration, thereby facilitating neointimal hyperplasia.</p><p><strong>Conclusions and implications: </strong>These findings demonstrate a critical role of mechanosensitive Piezo1 channel in neointimal hyperplasia via modulating VSMC phenotype. Piezo1 channels may represent a novel therapeutic target for maladaptive vascular remodelling and occlusive vascular diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}