Vascular pharmacology最新文献

{"title":"Recent advances in serum response factor posttranslational modifications and their therapeutic potential in cardiovascular and neurological diseases","authors":"Alexander Visconti ,&nbsp;Hongyu Qiu","doi":"10.1016/j.vph.2024.107421","DOIUrl":"10.1016/j.vph.2024.107421","url":null,"abstract":"<div><p>Serum Response Factor (SRF) is a key regulatory transcription factor present in various cell types throughout the body, playing essential roles in cellular functions under physiological conditions. Mutations and abnormal expression of SRF have been linked to the development of various diseases and disorders. Recent evidence highlights that post-translational modifications (PTMs) are critical for regulating SRF function in different cell types and contribute to disease pathogenesis. Targeting SRF-related PTMs is emerging as a promising therapeutic approach for treating SRF-associated diseases. In this review, we summarize recent advances in understanding SRF PTMs and their underlying regulatory mechanisms. We also explore the implications of SRF-PTM in related cardiovascular and neurological diseases and their potential for therapeutic intervention. This information underscores the significance of SRF PTMs in both physiological and pathological contexts, enhancing our understanding of disease mechanisms and paving the way for the development of novel therapeutic strategies.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107421"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098174","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":"Macrophages in vascular disease: Roles of mitochondria and metabolic mechanisms","authors":"Cameron D.A. Mackay ,&nbsp;Megan B. Meechem ,&nbsp;Vaibhav B. Patel","doi":"10.1016/j.vph.2024.107419","DOIUrl":"10.1016/j.vph.2024.107419","url":null,"abstract":"<div><p>Macrophages are a dynamic cell type of the immune system implicated in the pathophysiology of vascular diseases and are a major contributor to pathological inflammation. Excessive macrophage accumulation, activation, and polarization is observed in aortic aneurysm (AA), atherosclerosis, and pulmonary arterial hypertension. In general, macrophages become activated and polarized to a pro-inflammatory phenotype, which dramatically changes cell behavior to become pro-inflammatory and infiltrative. These cell types become cumbersome and fail to be cleared by normal mechanisms such as autophagy. The result is a hyper-inflammatory environment causing the recruitment of adjacent cells and circulating immune cells to further augment the inflammatory response. In AA, this leads to excessive ECM degradation and chemokine secretion, ultimately causing macrophages to dominate the immune cell landscape in the aortic wall. In atherosclerosis, monocytes are recruited to the vascular wall, where they polarize to the pro-inflammatory phenotype and induce inflammatory pathway activation. This leads to the development of foam cells, which significantly contribute to neointima and necrotic core formation in atherosclerotic plaques. Pro-inflammatory macrophages, which affect other vascular diseases, present with fragmented mitochondria and corresponding metabolic dysfunction. Targeting macrophage mitochondrial dynamics has proved to be an exciting potential therapeutic approach to combat vascular disease. This review will summarize mitochondrial and metabolic mechanisms of macrophage activation, polarization, and accumulation in vascular diseases.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107419"},"PeriodicalIF":3.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1537189124001459/pdfft?md5=6b29db26ffb2d1984f13c4a0b9fee3c4&pid=1-s2.0-S1537189124001459-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056707","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":"Characterization of a novel mitophagy-related 5-genes signature for diagnosis of acute myocardial infarction","authors":"Yanhua Xu ,&nbsp;Wenqing Zhu ,&nbsp;Yang Su ,&nbsp;Teng Ma ,&nbsp;Yaqi Zhang ,&nbsp;Xin Pan ,&nbsp;Rongrong Huang ,&nbsp;Yuhao Li ,&nbsp;Keqiang Zuo ,&nbsp;Sang-Bing Ong ,&nbsp;Dachun Xu","doi":"10.1016/j.vph.2024.107417","DOIUrl":"10.1016/j.vph.2024.107417","url":null,"abstract":"<div><p>Myocardial infarction (MI) and the ensuing heart failure (HF) remain the main cause of morbidity and mortality worldwide. One of the strategies to combat MI and HF lies in the ability to accurately predict the onset of these disorders. Alterations in mitochondrial homeostasis have been reported to be involved in the pathogenesis of various cardiovascular diseases (CVDs). In this regard, perturbations to mitochondrial dynamics leading to impaired clearance of dysfunctional mitochondria have been previously established to be a crucial trigger for MI/HF.</p><p>In this study, we found that MI patients could be classified into three clusters based on the expression levels of mitophagy-related genes and consensus clustering. We identified a mitophagy-related diagnostic 5-genes signature for MI using support vector machines-Recursive Feature Elimination (SVM-RFE) and random forest, with the area under the ROC curve (AUC) value of the predictive model at 0.813. Additionally, the single-cell transcriptome and pseudo-time analyses showed that the mitoscore was significantly upregulated in macrophages, endothelial cells, pericytes, fibroblasts and monocytes in patients with ischemic cardiomyopathy, while sequestosome 1 (SQSTM1) exhibited remarkable increase in the infarcted (ICM) and non-infarcted (ICMN) myocardium samples dissected from the left ventricle compared with control samples. Lastly, through analysis of peripheral blood from MI patients, we found that the expression of SQSTM1 is positively correlated with troponin-T (<em>P</em> &lt; 0.0001, <em>R</em> = 0.4195, R2 = 0.1759). Therefore, this study provides the rationale for a cell-specific mitophagy-related gene signature as an additional supporting diagnostic for CVDs.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107417"},"PeriodicalIF":3.5,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005474","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":"3-methoxycatechol causes vasodilation likely via KV channels: ex vivo, in silico docking and in vivo study","authors":"Patrícia Dias ,&nbsp;Rudy Salam ,&nbsp;Monika Moravcová ,&nbsp;Saina Saadat ,&nbsp;Jana Pourová ,&nbsp;Marie Vopršalová ,&nbsp;Eduard Jirkovský ,&nbsp;Jurjen Duintjer Tebbens ,&nbsp;Přemysl Mladěnka","doi":"10.1016/j.vph.2024.107418","DOIUrl":"10.1016/j.vph.2024.107418","url":null,"abstract":"<div><p>Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC₅₀s ranging from ∼10 to 24 μM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats <em>in vivo</em> without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca²⁺-channels. By using two inhibitors, activation of voltage-gated potassium channels (K_V) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the K_V7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107418"},"PeriodicalIF":3.5,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005473","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":"Association of serum 25-hydroxyvitamin D3 levels with carotid artery intima-media thickness and carotid atherosclerotic plaques in smokers","authors":"Yongjian Liu ,&nbsp;Yongbin Pei ,&nbsp;Shuowen Zhang,&nbsp;Zhixing Du,&nbsp;Litao Chen,&nbsp;Xiaojing Yan ,&nbsp;Jin Tian","doi":"10.1016/j.vph.2024.107416","DOIUrl":"10.1016/j.vph.2024.107416","url":null,"abstract":"<div><h3>Objective</h3><p>This study explores the association of serum 25-hydroxyvitamin D3 (25(OH)D3) levels with carotid artery intima-media thickness (CIMT), and the presence of carotid atherosclerotic plaques in individuals with a history of smoking.</p></div><div><h3>Methods</h3><p>A total of 469 patients suspected of having carotid atherosclerosis, aged 52 to 73 years with an average age of 65.26 ± 4.37 years, were recruited from the author's hospital from January 2023 to October 2023. All patients had a smoking history of nearly 5 years. Based on their serum 25(OH)D3 levels, they were divided into two groups: the normal group (serum level 30–50 ng/mL, <em>n</em> = 300) and the deficiency group (&lt;30 ng/mL, <em>n</em> = 169). General details of the two patient groups were collected. Carotid artery ultrasound was employed to assess pulse wave velocity (PWV), carotid artery compliance coefficient (CC), and CIMT. Blood chemistry analysis measured serum lipid metabolism indicators including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HD-LC). The relationship between CIMT and each variable was analyzed through Pearson correlation, and logistic regression was used to identify risk factors influencing carotid artery plaque development.</p></div><div><h3>Results</h3><p>General patient information between the two groups showed no significant differences (<em>P</em> &gt; 0.05). Patients in the 25(OH)D3 deficiency group exhibited elevated left and right PWV and CC compared to the 25(OH)D3 normal group (<em>P</em> &lt; 0.05). The deficiency group exhibited larger CIMT and plaque area compared to the normal group (<em>P</em> &lt; 0.05). Additionally, the deficiency group demonstrated higher levels of TC, LDL-C, and HD-LC compared to the normal group (<em>P</em> &lt; 0.05). A moderate positive correlation was found between TC, LDL-C, and CIMT (<em>P</em> &lt; 0.05), while a strong positive correlation existed between 25(OH)D3 and CIMT (P &lt; 0.05). In smokers, the formation of carotid artery plaque was associated with factors such as patient age, CIMT, serum LDL-C, and 25(OH)D3 levels (<em>P</em> &lt; 0.05). As age, CIMT, LDL-C levels increased, and 25(OH)D3 levels decreased, the risk of carotid plaques in smokers increased (<em>P</em> &lt; 0.05).</p></div><div><h3>Conclusions</h3><p>Smokers with lower 25(OH)D3 levels exhibit higher CIMT and more prominent carotid atherosclerotic plaques, indicating increased arterial stiffness and elevated cardiovascular risk. These findings demonstrate crucial implications that insufficient levels of vitamin D may potentially contribute to a higher risk of atherosclerosis among smokers.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107416"},"PeriodicalIF":3.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996565","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":"Disease mechanisms and therapeutic targets in pulmonary hypertension: Key insights from the special issue of vascular pharmacology on pulmonary hypertension","authors":"Beata Wojciak-Stothard ,&nbsp;Sachin Gupte ,&nbsp;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}