Vascular pharmacology最新文献

{"title":"Disease mechanisms and therapeutic targets in pulmonary hypertension: Key insights from the special issue of vascular pharmacology on pulmonary hypertension","authors":"Beata Wojciak-Stothard , Sachin Gupte , Eduardo Bossone","doi":"10.1016/j.vph.2024.107415","DOIUrl":"10.1016/j.vph.2024.107415","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107415"},"PeriodicalIF":3.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring bradykinin: A common mediator in the pathophysiology of sepsis and atherosclerotic cardiovascular disease","authors":"Mohd Zahari Siti-Zubaidah ,&nbsp;Harman-Shah Harafinova ,&nbsp;Abdullahi Nuradeen Liba ,&nbsp;Muhammad Luqman Nordin ,&nbsp;Kamarul Ariffin Hambali ,&nbsp;Hawa Nordin Siti","doi":"10.1016/j.vph.2024.107414","DOIUrl":"10.1016/j.vph.2024.107414","url":null,"abstract":"<div><p>Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical symptoms, both conditions share mechanisms mediated by bradykinin. This review explores bradykinin's role in inflammation, RAS modulation, and thrombosis in sepsis and ASCVD. In sepsis, variable kininogen-bradykinin levels may correlate with disease severity and progression, though the effect of bradykinin receptor modulation on inflammation remains uncertain. RAS activation is present in both diseases, with sepsis showing variable or low levels of Ang II, ACE, and ACE2, while ASCVD consistently exhibits elevated levels. Bradykinin may act as a mediator for ACE2 and AT2 receptor effects in RAS regulation. It may influence clotting and fibrinolysis in sepsis-associated coagulopathy, but evidence for an antithrombotic effect in ASCVD is insufficient. Understanding bradykinin's role in these shared pathologies could guide therapeutic and monitoring strategies and inform future research.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107414"},"PeriodicalIF":3.5,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel therapeutic targets for reperfusion injury in ischemic stroke: Understanding the role of mitochondria, excitotoxicity and ferroptosis","authors":"Vidhi Anupam Awasthi,&nbsp;Vaibhav Dhankar,&nbsp;Shamsher Singh","doi":"10.1016/j.vph.2024.107413","DOIUrl":"10.1016/j.vph.2024.107413","url":null,"abstract":"<div><p>Ischemic reperfusion injury (IRI) remains a significant challenge in various clinical settings, including stroke. Despite advances in reperfusion strategies, the restoration of blood flow to ischemic tissues often exacerbates tissue damage through a complex cascade of cellular and molecular events. In recent years, there has been growing interest in identifying novel therapeutic targets to ameliorate the detrimental effects of IRI and improve patient outcomes. This review critically evaluates emerging therapeutic targets and strategies for IRI management, such as R-spondin 3, neurolysin, glial cell gene therapy and inter alpha inhibitors. Diverse pathophysiology involved in IRI stroke such as oxidative stress, inflammation, mitochondrial dysfunction, and ferroptosis are also closely discussed. Additionally, we explored the intricate interplay between inflammation and IRI, focusing on cell-mediated gene therapy approaches and anti-inflammatory agents that hold promise for attenuating tissue damage. Moreover, we delve into novel strategies aimed at preserving endothelial function, promoting tissue repair, and enhancing cellular resilience to ischemic insults. Finally, we discuss challenges, future directions, and translational opportunities for the development of effective therapies targeting ischemic reperfusion injury.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107413"},"PeriodicalIF":3.5,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac biogenic amine profile and its relationship with parameters of cardiovascular disease in obesity","authors":"Matheus Antônio Filiol Belin ,&nbsp;Taynara Aparecida Vieira ,&nbsp;Núbia Alves Grandini ,&nbsp;Juliana Silva Siqueira ,&nbsp;Thiago Luiz Novaga Palacio ,&nbsp;Jordanna Cruzeiro ,&nbsp;Luis Eduardo Sormani ,&nbsp;Murilo Dalarme Tanganini ,&nbsp;Gabriela Souza Barbosa ,&nbsp;Cristina Schmitt Gregolin ,&nbsp;Dijon Henrique Salomé de Campos ,&nbsp;Silmeia Garcia Zanati Bazan ,&nbsp;Igor Otávio Minatel ,&nbsp;Giuseppina Pace Pereira Lima ,&nbsp;Camila Renata Correa","doi":"10.1016/j.vph.2024.107412","DOIUrl":"10.1016/j.vph.2024.107412","url":null,"abstract":"<div><h3>Aims</h3><p>To identify the cardiac biogenic amine profile of obese rats and associate these compounds with parameters of cardiovascular disease.</p></div><div><h3>Main methods</h3><p>Wistar rats (<em>n</em> = 20) were randomly distributed into two groups: control and obese. Obesity was induced by a high-sugar fat diet. Biochemical parameters were evaluated. Doppler Echocardiography and systolic blood pressure; interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), protein carbonylation, ferric reducing antioxidant power (FRAP), and catalase activity were measured in cardiac tissue. HPLC evaluated the cardiac biogenic profile. Data were compared using the Student's T or Mann-Whitney tests and Spearman's correlation at 5% significance. The principal component analysis (PCA) was performed.</p></div><div><h3>Key findings</h3><p>Obesity generated hypertension, cardiac remodeling and dysfunction, and imbalanced all biochemical, inflammatory, and oxidative markers (<em>p</em> &lt; 0.001). Eight biogenic amines were found in cardiac tissue. Obesity increased serotonin and decreased agmatine, putrescine, cadaverine, and spermidine. Serotonin (<em>r</em> = 0.534 to 0.808) was strong and positively correlated with obesity, biochemical parameters, cardiac inflammation, oxidative stress, hypertension, cardiac remodeling, and dysfunction (<em>p</em> &lt; 0.001). Spermidine (<em>r</em> = −0.560 to −0.680), putrescine (<em>r</em> = −0.532 to −0.805), cadaverine (<em>r</em> = −0.534 to −0.860), and agmatine (<em>r</em> = −0.579 to −0.884) were inversely correlated with the same parameters (<em>p</em> &lt; 0.001). PCA allowed for distinguishing the control and obese groups.</p></div><div><h3>Significance</h3><p>There are strong correlations between cardiac biogenic amine levels, cardiac remodeling, and dysfunction resulting from obesity.</p></div><div><h3>Conclusion</h3><p>There is an association between cardiac biogenic amines and cardiovascular disease in obesity. In addition, agmatine, putrescine, cadaverine, and, mainly, serotonin may be new biomarkers for cardiovascular health in obesity and help to improve the diagnosis and treatment of CVD resulting or not from obesity. However, more research is needed to support this conclusion.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107412"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients","authors":"Stefano Ministrini ,&nbsp;Rebecca Niederberger ,&nbsp;Alexander Akhmedov ,&nbsp;Georgia Beer ,&nbsp;Yustina M. Puspitasari ,&nbsp;Maria Franzini ,&nbsp;Giuseppe Vergaro ,&nbsp;Douglas E. Cannie ,&nbsp;Perry Elliott ,&nbsp;Peter C. Kahr ,&nbsp;Christoph Hock ,&nbsp;Richard Kobza ,&nbsp;Stefan Toggweiler ,&nbsp;Thomas F. Lüscher ,&nbsp;Giovanni G. Camici ,&nbsp;Simon F. Stämpfli","doi":"10.1016/j.vph.2024.107411","DOIUrl":"10.1016/j.vph.2024.107411","url":null,"abstract":"<div><h3>Introduction</h3><p>Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect.</p></div><div><h3>Methods</h3><p>Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction.</p></div><div><h3>Results</h3><p>Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF.</p></div><div><h3>Conclusions</h3><p>Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107411"},"PeriodicalIF":3.5,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium nitroprusside infusion in patients with advanced heart failure","authors":"Stefano Ghio ,&nbsp;Egidio Traversi ,&nbsp;Roberto Maestri ,&nbsp;Rita Camporotondo ,&nbsp;Angelo Caporotondi ,&nbsp;Alessandra Caprino ,&nbsp;Alessandro Fasolino ,&nbsp;Giampaolo Guazzotti ,&nbsp;Laura Scelsi ,&nbsp;Annalisa Turco ,&nbsp;Maria Teresa La Rovere","doi":"10.1016/j.vph.2024.107395","DOIUrl":"10.1016/j.vph.2024.107395","url":null,"abstract":"<div><h3>Aims</h3><p>Advanced heart failure (AdvHF) poses significant treatment challenges, particularly when mechanical circulatory support or transplant options are unavailable, highlighting a gap in evidence-based medical management. The aim of this study was to evaluate the safety and effectiveness of sodium nitroprusside infusion (SNP) for enhancing systemic and renal perfusion in patients with AdvHF, with or without concomitant inotropic support.</p></div><div><h3>Methods and results</h3><p>We retrospectively analyzed the medical records of 406 patients with AdvHF admitted between October 2014 and September 2018 who received nocturnal SNP infusions for at least one week. In 55 patients with symptomatic hypotension or signs of peripheral hypoperfusion (differential systemic BP &lt; 15 mmHg), continuous dobutamine infusion was added. In a subset of 155 patients who required multiple hospitalizations (median 3), data from the last hospitalization were used. No symptomatic hypotension leading to discontinuation of SNP (mean dose: 0.5 ± 0.1 μg/kg/min) was reported. Patients showed a significant increase in differential systemic blood pressure after infusion (29.2 ± 8.1 to 36.8 ± 11.6 mmHg, <em>p</em> &lt; 0.001) independent of dobutamine use.</p><p>Administration of SNP and dobutamine resulted in greater weight loss compared to SNP alone (−5.33 ± 7.02 vs −3.32 ± 4.0 kg, <em>p</em> &lt; 0.003), but it was also associated with a significant increase in creatinine levels compared to SNP alone (+0.24 ± 0.87 vs +0.02 ± 0.43, <em>p</em> = 0.005).</p></div><div><h3>Conclusions</h3><p>The results show that SNP is a safe therapeutic choice in AdvHF patients with or without concomitant inotropic support and highlight the potential efficacy of nitroprusside in improving systemic and renal perfusion in these advanced patients.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107395"},"PeriodicalIF":3.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc alpha 2-glycoprotein associates with features of plaque stability in patients with carotid atherosclerosis","authors":"Amedeo Tirandi ,&nbsp;Federico Carbone ,&nbsp;Aldo Bonaventura ,&nbsp;Maria Bertolotto ,&nbsp;Silvia Minetti ,&nbsp;Simon Kraler ,&nbsp;Giovanni G. Camici ,&nbsp;Fabrizio Montecucco ,&nbsp;Luca Liberale","doi":"10.1016/j.vph.2024.107398","DOIUrl":"10.1016/j.vph.2024.107398","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107398"},"PeriodicalIF":3.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorinated perhexiline derivative attenuates vascular proliferation in pulmonary arterial hypertension smooth muscle cells","authors":"Kayleigh Griffiths ,&nbsp;Roger J. Grand ,&nbsp;Ian Horan ,&nbsp;Michelangelo Certo ,&nbsp;Ross C. Keeler ,&nbsp;Claudio Mauro ,&nbsp;Chih-Chung Tseng ,&nbsp;Iain Greig ,&nbsp;Nicholas W. Morrell ,&nbsp;Matteo Zanda ,&nbsp;Michael P. Frenneaux ,&nbsp;Melanie Madhani","doi":"10.1016/j.vph.2024.107399","DOIUrl":"10.1016/j.vph.2024.107399","url":null,"abstract":"<div><p>Increased proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs) is recognised as a universal hallmark of pulmonary arterial hypertension (PAH), in part related to the association with reduced pyruvate dehydrogenase (PDH) activity, resulting in decreased oxidative phosphorylation of glucose and increased aerobic glycolysis (Warburg effect). Perhexiline is a well-recognised carnitine palmitoyltransferase-1 (CPT1) inhibitor used in cardiac diseases, which reciprocally increases PDH activity, but is associated with variable pharmacokinetics related to polymorphic variation of the cytochrome P450-2D6 (CYP2D6) enzyme, resulting in the risk of neuro and hepatotoxicity in ‘slow metabolisers’ unless blood levels are monitored and dose adjusted. We have previously reported that a novel perhexiline fluorinated derivative (FPER-1) has the same therapeutic profile as perhexiline but is not metabolised by CYP2D6, resulting in more predictable pharmacokinetics than the parent drug. We sought to investigate the effects of perhexiline and FPER-1 on PDH flux in PASMCs from patients with PAH. We first confirmed that PAH PASMCs exhibited increased cell proliferation, enhanced phosphorylation of AKT^Ser473, ERK 1/2^{Thr202/Tyr204} and PDH-E1α^Ser293, indicating a Warburg effect when compared to healthy PASMCs. Pre-treatment with perhexiline or FPER-1 significantly attenuated PAH PASMC proliferation in a concentration-dependent manner and suppressed the activation of the AKT^Ser473 but had no effect on the ERK pathway. Perhexiline and FPER-1 markedly activated PDH (seen as dephosphorylation of PDH-E1α^Ser293), reduced glycolysis, and upregulated mitochondrial respiration in these PAH PASMCs as detected by Seahorse analysis. However, both perhexiline and FPER-1 did not induce apoptosis as measured by caspase 3/7 activity. We show for the first time that both perhexiline and FPER-1 may represent therapeutic agents for reducing cell proliferation in human PAH PASMCs, by reversing Warburg physiology.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107399"},"PeriodicalIF":3.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1537189124001253/pdfft?md5=8391d72e7918e2a189c9e5ed43fb60e6&pid=1-s2.0-S1537189124001253-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ex vivo study on the human blood neutrophil circadian features and effects of alpha1-antitrypsin and lipopolysaccharide","authors":"Julia Held ,&nbsp;Kokilavani Sivaraman ,&nbsp;Sabine Wrenger ,&nbsp;Wenzhang Si ,&nbsp;Tobias Welte ,&nbsp;Stephan Immenschuh ,&nbsp;Sabina Janciauskiene","doi":"10.1016/j.vph.2024.107396","DOIUrl":"10.1016/j.vph.2024.107396","url":null,"abstract":"<div><h3>Aims</h3><p>Neutrophils perform various functions in a circadian-dependent manner; therefore, we investigated here whether the effect of alpha1-antitrypsin (AAT), used as augmentation therapy, is dependent on the neutrophil circadian clock. AAT is a vital regulator of neutrophil functions, and its qualitative and/or quantitative defects have significant implications for the development of respiratory diseases.</p></div><div><h3>Methods</h3><p>Whole blood from 12 healthy women age years, mean (SD) 29.92 (5.48) was collected twice daily, 8 h apart, and incubated for 30 min at 37 °C alone or with additions of 2 mg/ml AAT (Respreeza) and/or 5 μg/ml lipopolysaccharide (LPS) from <em>Escherichia coli</em>. Neutrophils were then isolated to examine gene expression, migration and phagocytosis.</p></div><div><h3>Results</h3><p>The expression of <em>CD14</em>, <em>CD16</em>, <em>CXCR2</em> and <em>SELL</em> (encoding CD62L) genes was significantly higher while <em>CDKN1A</em> lower in the afternoon than in the morning neutrophils from untreated blood. Neutrophils isolated in the afternoon had higher migratory and phagocytic activity. Morning neutrophils isolated from AAT-pretreated blood showed higher expression of <em>CXCR2</em> and <em>SELL</em> than those from untreated morning blood. Pretreatment of blood with AAT enhanced migratory properties of morning but not afternoon neutrophils. Of all genes analysed, only <em>CXCL8</em> expression was strongly upregulated in morning and afternoon neutrophils isolated from LPS-pretreated blood, whereas <em>CXCR2</em> expression was downregulated in afternoon neutrophils. The addition of AAT did not reverse the effects of LPS.</p></div><div><h3>Significance</h3><p>The circadian clock of myeloid cells may affect the effectiveness of various therapies, including AAT therapy used to treat patients with AAT deficiency, and needs further investigation.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107396"},"PeriodicalIF":3.5,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel NLRP3 inhibitor INF195: Low doses provide effective protection against myocardial ischemia/reperfusion injury","authors":"Simone Gastaldi ,&nbsp;Magalì Giordano ,&nbsp;Federica Blua ,&nbsp;Chiara Rubeo ,&nbsp;Valentina Boscaro ,&nbsp;Saveria Femminò ,&nbsp;Stefano Comità ,&nbsp;Eleonora Gianquinto ,&nbsp;Vanessa Landolfi ,&nbsp;Elisabetta Marini ,&nbsp;Margherita Gallicchio ,&nbsp;Francesca Spyrakis ,&nbsp;Pasquale Pagliaro ,&nbsp;Massimo Bertinaria ,&nbsp;Claudia Penna","doi":"10.1016/j.vph.2024.107397","DOIUrl":"10.1016/j.vph.2024.107397","url":null,"abstract":"<div><h3>Background</h3><p>Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and caspase-1. However, NLRP3 may paradoxically exhibit cardioprotective properties. This study aimed to assess the protective effects of the novel NLRP3 inhibitor, INF195, both <em>in vitro</em> and <em>ex vivo</em>.</p></div><div><h3>Methods</h3><p>To investigate the relationship between NLRP3 and myocardial IRI, we synthetized a series of novel NLRP3 inhibitors, and investigated their putative binding mode <em>via</em> docking studies. Through <em>in vitro</em> studies we identified INF195 as optimal for NLRP3 inhibition. We measured infarct-size in isolated mouse hearts subjected to 30-min global ischemia/one-hour reperfusion in the presence of three different doses of INF195 (5, 10, or 20-μM). We analyzed caspase-1 and IL-1β concentration in cardiac tissue homogenates by ELISA. Statistical significance was determined using one-way ANOVA followed by Tukey's test.</p></div><div><h3>Results and conclusion</h3><p>INF195 reduces NLRP3-induced pyroptosis in human macrophages. Heart pre-treatment with 5 and 10-μM INF195 significantly reduces both infarct size and IL-1β levels. Data suggest that intracardiac NLRP3 activation contributes to IRI and that low doses of INF195 exert cardioprotective effects by reducing infarct size. However, at 20-μM, INF195 efficacy declines, leading to a lack of cardioprotection. Research is required to determine if high doses of INF195 have off-target effects or dual roles, potentially eliminating both harmful and cardioprotective functions of NLRP3. Our findings highlight the potential of a new chemical scaffold, amenable to further optimization, to provide NLRP3 inhibition and cardioprotection in the ischemia/reperfusion setting.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107397"},"PeriodicalIF":3.5,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S153718912400123X/pdfft?md5=7b2301213b9f44bacdfc9fe1a9b13cfa&pid=1-s2.0-S153718912400123X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}