Pub Date : 2024-12-19DOI: 10.1016/j.vph.2024.107459
J. Anakha, Yenisetti Rajendra Prasad, Abhay H. Pande
Angiogenesis plays a pivotal role in various pathological conditions, making it a key target in therapeutic development. Anti-angiogenic therapies are gaining traction for their potential in treating a range of angiogenesis-dependent diseases. Among these, endogenous angiogenesis inhibitors, particularly endostatin, have garnered significant attention for their therapeutic potential. While extensively studied for its anti-angiogenic effects in cancer, endostatin also exhibits anti-atherosclerotic and anti-fibrotic properties, broadening its therapeutic scope. Despite the successful clinical use of recombinant human endostatin in China for nearly two decades, its broader therapeutic potential remains underexplored. Thus, this review delves into the multifaceted applications of endostatin, examining its role in ocular diseases, inflammation, reproductive disorders, and tumor angiogenesis. Furthermore, it provides a comprehensive overview of its emerging roles beyond angiogenesis, particularly in the context of atherosclerosis and fibroproliferative conditions.
{"title":"Endostatin in disease modulation: From cancer to beyond","authors":"J. Anakha, Yenisetti Rajendra Prasad, Abhay H. Pande","doi":"10.1016/j.vph.2024.107459","DOIUrl":"10.1016/j.vph.2024.107459","url":null,"abstract":"<div><div>Angiogenesis plays a pivotal role in various pathological conditions, making it a key target in therapeutic development. Anti-angiogenic therapies are gaining traction for their potential in treating a range of angiogenesis-dependent diseases. Among these, endogenous angiogenesis inhibitors, particularly endostatin, have garnered significant attention for their therapeutic potential. While extensively studied for its anti-angiogenic effects in cancer, endostatin also exhibits anti-atherosclerotic and anti-fibrotic properties, broadening its therapeutic scope. Despite the successful clinical use of recombinant human endostatin in China for nearly two decades, its broader therapeutic potential remains underexplored. Thus, this review delves into the multifaceted applications of endostatin, examining its role in ocular diseases, inflammation, reproductive disorders, and tumor angiogenesis. Furthermore, it provides a comprehensive overview of its emerging roles beyond angiogenesis, particularly in the context of atherosclerosis and fibroproliferative conditions.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107459"},"PeriodicalIF":3.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873024","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}
Pub Date : 2024-12-17DOI: 10.1016/j.vph.2024.107458
Simona Scorza , Valentina Brunetti , Giorgia Scarpellino , Maira Certini , Andrea Gerbino , Francesco Moccia
Ca2+ signaling events are essential for maintaining cardiovascular health, regulating critical functions in both endothelial and cardiac cells. SARS-CoV-2 infection impinges this delicate balance, leading to severe cardiovascular complications. SARS-CoV-2 binds to the ACE2 receptor on endothelial and cardiomyocyte surfaces, triggering abnormal increases in intracellular Ca2+ levels that promote endothelial dysfunction, inflammation, and hypercoagulation. In endothelial cells, this dysregulation activates a pro-inflammatory state and compromises vascular integrity. In cardiomyocytes, SARS-CoV-2-induced Ca2+ imbalances contribute to arrhythmias and heart failure by promoting abnormal Ca2+ cycling and energy metabolism disruptions. Additionally, the cytokine storm associated with COVID-19 amplifies these effects by further altering Ca2+ handling, enhancing inflammatory responses, and promoting thrombosis. Targeting Ca2+ channels, particularly endolysosomal two-pore channels, represents a promising therapeutic approach to counteract SARS-CoV-2’s effects on Ca2+ dynamics. Several FDA-approved drugs that modulate Ca2+ signaling could be repurposed to prevent viral entry and mitigate cardiovascular damage. Understanding these Ca2+-related mechanisms offers valuable insights for developing treatments to reduce cardiovascular risk in COVID-19 and potentially future viral infections impacting the cardiovascular system.
{"title":"Targeting the Ca2+ signaling toolkit as an alternative strategy to mitigate SARS-CoV-2-induced cardiovascular adverse events","authors":"Simona Scorza , Valentina Brunetti , Giorgia Scarpellino , Maira Certini , Andrea Gerbino , Francesco Moccia","doi":"10.1016/j.vph.2024.107458","DOIUrl":"10.1016/j.vph.2024.107458","url":null,"abstract":"<div><div>Ca<sup>2+</sup> signaling events are essential for maintaining cardiovascular health, regulating critical functions in both endothelial and cardiac cells. SARS-CoV-2 infection impinges this delicate balance, leading to severe cardiovascular complications. SARS-CoV-2 binds to the ACE2 receptor on endothelial and cardiomyocyte surfaces, triggering abnormal increases in intracellular Ca<sup>2+</sup> levels that promote endothelial dysfunction, inflammation, and hypercoagulation. In endothelial cells, this dysregulation activates a pro-inflammatory state and compromises vascular integrity. In cardiomyocytes, SARS-CoV-2-induced Ca<sup>2+</sup> imbalances contribute to arrhythmias and heart failure by promoting abnormal Ca<sup>2+</sup> cycling and energy metabolism disruptions. Additionally, the cytokine storm associated with COVID-19 amplifies these effects by further altering Ca<sup>2+</sup> handling, enhancing inflammatory responses, and promoting thrombosis. Targeting Ca<sup>2+</sup> channels, particularly endolysosomal two-pore channels, represents a promising therapeutic approach to counteract SARS-CoV-2’s effects on Ca<sup>2+</sup> dynamics. Several FDA-approved drugs that modulate Ca<sup>2+</sup> signaling could be repurposed to prevent viral entry and mitigate cardiovascular damage. Understanding these Ca<sup>2+</sup>-related mechanisms offers valuable insights for developing treatments to reduce cardiovascular risk in COVID-19 and potentially future viral infections impacting the cardiovascular system.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107458"},"PeriodicalIF":3.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865441","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}
Pub Date : 2024-12-11DOI: 10.1016/j.vph.2024.107457
Siarhei A. Dabravolski , Alexey V. Churov , Alessio L. Ravani , Amina E. Karimova , Igor G. Luchinkin , Vasily N. Sukhorukov , Alexander N. Orekhov
Atherosclerosis is a multifaceted disease characterised by chronic inflammation and vascular remodelling, leading to plaque formation and cardiovascular complications. Recent evidence highlights the critical role of epsins, a family of endocytic proteins, in the pathogenesis of atherosclerosis. This manuscript explores the multifarious functions of epsins in atherosclerosis, focusing on their involvement in angiogenesis, lymphangiogenesis, and the modulation of key signalling pathways. We discuss how epsins facilitate EndoMT through their interaction with the TGFβ signalling pathway, which contributes to vascular smooth muscle cell-like phenotypes and plaque instability. Additionally, we examine the therapeutic potential of targeting epsins, elucidating their interactions with crucial partners such as LDLR, LRP-1, and TLR 2/4, among others, in mediating lipid metabolism and inflammation. Furthermore, we highlight the promising prospects of epsin-targeting peptides and small interfering RNAs as therapeutic agents for atherosclerosis treatment. Despite these advancements, the research faces limitations, including a reliance on specific mouse models and a need for comprehensive studies on the long-term effects of epsin modulation. Therefore, future investigations should focus on elucidating the detailed mechanisms of epsin function and their implications in cardiovascular health, fostering collaborations to translate basic research into innovative therapeutic strategies. This work underscores the necessity for further exploration of epsins to unlock their full therapeutic potential in combating atherosclerosis and related cardiovascular diseases.
{"title":"The role of Epsins in atherosclerosis: From molecular mechanisms to therapeutic applications","authors":"Siarhei A. Dabravolski , Alexey V. Churov , Alessio L. Ravani , Amina E. Karimova , Igor G. Luchinkin , Vasily N. Sukhorukov , Alexander N. Orekhov","doi":"10.1016/j.vph.2024.107457","DOIUrl":"10.1016/j.vph.2024.107457","url":null,"abstract":"<div><div>Atherosclerosis is a multifaceted disease characterised by chronic inflammation and vascular remodelling, leading to plaque formation and cardiovascular complications. Recent evidence highlights the critical role of epsins, a family of endocytic proteins, in the pathogenesis of atherosclerosis. This manuscript explores the multifarious functions of epsins in atherosclerosis, focusing on their involvement in angiogenesis, lymphangiogenesis, and the modulation of key signalling pathways. We discuss how epsins facilitate EndoMT through their interaction with the TGFβ signalling pathway, which contributes to vascular smooth muscle cell-like phenotypes and plaque instability. Additionally, we examine the therapeutic potential of targeting epsins, elucidating their interactions with crucial partners such as LDLR, LRP-1, and TLR 2/4, among others, in mediating lipid metabolism and inflammation. Furthermore, we highlight the promising prospects of epsin-targeting peptides and small interfering RNAs as therapeutic agents for atherosclerosis treatment. Despite these advancements, the research faces limitations, including a reliance on specific mouse models and a need for comprehensive studies on the long-term effects of epsin modulation. Therefore, future investigations should focus on elucidating the detailed mechanisms of epsin function and their implications in cardiovascular health, fostering collaborations to translate basic research into innovative therapeutic strategies. This work underscores the necessity for further exploration of epsins to unlock their full therapeutic potential in combating atherosclerosis and related cardiovascular diseases.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107457"},"PeriodicalIF":3.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822174","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}
Pub Date : 2024-12-10DOI: 10.1016/j.vph.2024.107452
Dimitris Kardassis , Cécile Vindis , Camelia Sorina Stancu , Laura Toma , Anca Violeta Gafencu , Adriana Georgescu , Nicoleta Alexandru-Moise , Filippo Molica , Brenda R. Kwak , Alexandrina Burlacu , Ignacio Fernando Hall , Elena Butoi , Paolo Magni , Junxi Wu , Susana Novella , Luke F. Gamon , Michael J. Davies , Andrea Caporali , Fernando de la Cuesta , Tijana Mitić
Despite the discovery and prevalent clinical use of potent lipid-lowering therapies, including statins and PCSK9 inhibitors, cardiovascular diseases (CVD) caused by atherosclerosis remain a large unmet clinical need, accounting for frequent deaths worldwide. The pathogenesis of atherosclerosis is a complex process underlying the presence of modifiable and non-modifiable risk factors affecting several cell types including endothelial cells (ECs), monocytes/macrophages, smooth muscle cells (SMCs) and T cells. Heterogeneous composition of the plaque and its morphology could lead to rupture or erosion causing thrombosis, even a sudden death. To decipher this complexity, various cell model systems have been developed. With recent advances in systems biology approaches and single or multi-omics methods researchers can elucidate specific cell types, molecules and signalling pathways contributing to certain stages of disease progression. Compared with animals, in vitro models are economical, easily adjusted for high-throughput work, offering mechanistic insights. Hereby, we review the latest work performed employing the cellular models of atherosclerosis to generate a variety of omics data. We summarize their outputs and the impact they had in the field. Challenges in the translatability of the omics data obtained from the cell models will be discussed along with future perspectives.
{"title":"Unravelling molecular mechanisms in atherosclerosis using cellular models and omics technologies","authors":"Dimitris Kardassis , Cécile Vindis , Camelia Sorina Stancu , Laura Toma , Anca Violeta Gafencu , Adriana Georgescu , Nicoleta Alexandru-Moise , Filippo Molica , Brenda R. Kwak , Alexandrina Burlacu , Ignacio Fernando Hall , Elena Butoi , Paolo Magni , Junxi Wu , Susana Novella , Luke F. Gamon , Michael J. Davies , Andrea Caporali , Fernando de la Cuesta , Tijana Mitić","doi":"10.1016/j.vph.2024.107452","DOIUrl":"10.1016/j.vph.2024.107452","url":null,"abstract":"<div><div>Despite the discovery and prevalent clinical use of potent lipid-lowering therapies, including statins and PCSK9 inhibitors, cardiovascular diseases (CVD) caused by atherosclerosis remain a large unmet clinical need, accounting for frequent deaths worldwide. The pathogenesis of atherosclerosis is a complex process underlying the presence of modifiable and non-modifiable risk factors affecting several cell types including endothelial cells (ECs), monocytes/macrophages, smooth muscle cells (SMCs) and T cells. Heterogeneous composition of the plaque and its morphology could lead to rupture or erosion causing thrombosis, even a sudden death. To decipher this complexity, various cell model systems have been developed. With recent advances in systems biology approaches and single or multi-omics methods researchers can elucidate specific cell types, molecules and signalling pathways contributing to certain stages of disease progression. Compared with animals, <em>in vitro</em> models are economical, easily adjusted for high-throughput work, offering mechanistic insights. Hereby, we review the latest work performed employing the cellular models of atherosclerosis to generate a variety of omics data. We summarize their outputs and the impact they had in the field. Challenges in the translatability of the omics data obtained from the cell models will be discussed along with future perspectives.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107452"},"PeriodicalIF":3.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818826","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}
Pub Date : 2024-12-03DOI: 10.1016/j.vph.2024.107444
Er Jin , Bei Li , Xiaonan Wang , Runlan Yan , Chenhong Yan , Yue Gao
Objective
In some reports, antiphospholipid antibodies (aPL) prevalence is higher in COVID-19 patients. This study intended to compare aPL prevalence between COVID-19 patients and healthy controls, and differences in aPL types using meta-analysis.
Methods
This work retrieved published literature about association between COVID-19 and aPL from Embase, Web of Science, PubMed, and The Cochrane Library databases. The observation group was COVID-19 patients, and the control group was healthy individuals. Outcome measures contained any of following aPLs: classic aPL: anti-cardiolipin antibodies (aCL) and anti-β2-glycoprotein-1 antibodies (Anti-β2GP1); other non-criteria aPL: anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and anti-annexin-V antibodies (AnV). Meta-analysis was done on Review Manager 5.4.
Results
10 studies involving 2288 patients were deemed eligible for inclusion. The results of the meta-analysis showed that the prevalence of Classic aPL and Any aPL in the COVID-19 group was significantly higher than in the healthy group (Classic aPL, RR = 2.55, 95 % CI = 1.83–3.55, P < 0.00001; Any aPL, RR = 2.34, 95 % CI = 1.46–3.77, P = 0.0005). Anti-β2GP1 IgA antibodies were the most common aPL in COVID-19 patients, with a significantly higher prevalence than in the healthy group (RR = 4.26, 95 % CI = 2.84–6.40, P < 0.00001). The prevalence of the four types of IgM aPL was significantly higher in the COVID-19 group compared to the healthy group, while there was no significant difference in aPL IgG between the two groups.
Conclusion
The prevalence of aPL in COVID-19 patients was significantly higher than in the healthy control group. IgM aPL was more easily detectable in the early stages of COVID-19 infection, while IgG aPL may be of more concern in the later time points of the immune epidemiology following SARS-CoV-2 infection.
{"title":"Prevalence of antiphospholipid antibodies in COVID-19 patients: A meta-analysis","authors":"Er Jin , Bei Li , Xiaonan Wang , Runlan Yan , Chenhong Yan , Yue Gao","doi":"10.1016/j.vph.2024.107444","DOIUrl":"10.1016/j.vph.2024.107444","url":null,"abstract":"<div><h3>Objective</h3><div>In some reports, antiphospholipid antibodies (aPL) prevalence is higher in COVID-19 patients. This study intended to compare aPL prevalence between COVID-19 patients and healthy controls, and differences in aPL types using meta-analysis.</div></div><div><h3>Methods</h3><div>This work retrieved published literature about association between COVID-19 and aPL from Embase, Web of Science, PubMed, and The Cochrane Library databases. The observation group was COVID-19 patients, and the control group was healthy individuals. Outcome measures contained any of following aPLs: classic aPL: anti-cardiolipin antibodies (aCL) and anti-β2-glycoprotein-1 antibodies (Anti-β2GP1); other non-criteria aPL: anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and anti-annexin-V antibodies (AnV). Meta-analysis was done on Review Manager 5.4.</div></div><div><h3>Results</h3><div>10 studies involving 2288 patients were deemed eligible for inclusion. The results of the meta-analysis showed that the prevalence of Classic aPL and Any aPL in the COVID-19 group was significantly higher than in the healthy group (Classic aPL, RR = 2.55, 95 % CI = 1.83–3.55, <em>P</em> < 0.00001; Any aPL, RR = 2.34, 95 % CI = 1.46–3.77, <em>P</em> = 0.0005). Anti-β2GP1 IgA antibodies were the most common aPL in COVID-19 patients, with a significantly higher prevalence than in the healthy group (RR = 4.26, 95 % CI = 2.84–6.40, <em>P</em> < 0.00001). The prevalence of the four types of IgM aPL was significantly higher in the COVID-19 group compared to the healthy group, while there was no significant difference in aPL IgG between the two groups.</div></div><div><h3>Conclusion</h3><div>The prevalence of aPL in COVID-19 patients was significantly higher than in the healthy control group. IgM aPL was more easily detectable in the early stages of COVID-19 infection, while IgG aPL may be of more concern in the later time points of the immune epidemiology following SARS-CoV-2 infection.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"158 ","pages":"Article 107444"},"PeriodicalIF":3.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787324","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}
Post-percutaneous coronary intervention (PCI) patients often require complex medication regimens to prevent adverse cardiovascular events. However, these regimens can lead to potential drug-drug interactions (pDDIs) and polypharmacy, posing significant clinical challenges. This study aims to evaluate the pattern of medication use, prevalence, and correlates of pDDIs and polypharmacy among post-PCI patients in Shiraz, Iran.
Methods
A cross-sectional study was conducted on 9019 PCI patients in Shiraz. Patient data, including demographics, medical history, and medication lists, were collected and analyzed. The Anatomical Therapeutic Chemical (ATC) classification system was applied. pDDIs were identified using the Lexicomp database, and their severity was classified. Factors associated with significant pDDIs and polypharmacy were assessed using multivariable modeling.
Results
The study found that 91.6 % of patients received statin prescriptions and 94.5 % were on antiplatelet therapy. Notably, 82.8 % were identified with at least one pDDI, with 80.4 % having significant interactions (Categories C, D, or X). Common potential interactions included aspirin with clopidogrel and rosuvastatin. Polypharmacy was prevalent in 73.6 % of patients, associated with higher risks of interactions. Factors such as polypharmacy, male gender, diabetes mellitus, and heart failure were significant predictors of pDDIs.
Conclusions
The study underscores the high prevalence of pDDIs and polypharmacy among post-PCI patients, revealing a critical gap between clinical guidelines and drug interaction databases. Updating interaction databases to reflect current clinical practices and enhancing collaboration between database developers and guideline authors are essential for improving medication safety and patient outcomes.
{"title":"Patterns of medication use and potential drug-drug interactions in post-PCI patients: A study from Iran","authors":"Reza Golchin Vafa , Hossein Molavi Vardanjani , Javad Kojuri","doi":"10.1016/j.vph.2024.107441","DOIUrl":"10.1016/j.vph.2024.107441","url":null,"abstract":"<div><h3>Background</h3><div>Post-percutaneous coronary intervention (PCI) patients often require complex medication regimens to prevent adverse cardiovascular events. However, these regimens can lead to potential drug-drug interactions (pDDIs) and polypharmacy, posing significant clinical challenges. This study aims to evaluate the pattern of medication use, prevalence, and correlates of pDDIs and polypharmacy among post-PCI patients in Shiraz, Iran.</div></div><div><h3>Methods</h3><div>A cross-sectional study was conducted on 9019 PCI patients in Shiraz. Patient data, including demographics, medical history, and medication lists, were collected and analyzed. The Anatomical Therapeutic Chemical (ATC) classification system was applied. pDDIs were identified using the Lexicomp database, and their severity was classified. Factors associated with significant pDDIs and polypharmacy were assessed using multivariable modeling.</div></div><div><h3>Results</h3><div>The study found that 91.6 % of patients received statin prescriptions and 94.5 % were on antiplatelet therapy. Notably, 82.8 % were identified with at least one pDDI, with 80.4 % having significant interactions (Categories C, D, or X). Common potential interactions included aspirin with clopidogrel and rosuvastatin. Polypharmacy was prevalent in 73.6 % of patients, associated with higher risks of interactions. Factors such as polypharmacy, male gender, diabetes mellitus, and heart failure were significant predictors of pDDIs.</div></div><div><h3>Conclusions</h3><div>The study underscores the high prevalence of pDDIs and polypharmacy among post-PCI patients, revealing a critical gap between clinical guidelines and drug interaction databases. Updating interaction databases to reflect current clinical practices and enhancing collaboration between database developers and guideline authors are essential for improving medication safety and patient outcomes.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107441"},"PeriodicalIF":3.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710830","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}
Pub Date : 2024-12-01DOI: 10.1016/j.vph.2024.107443
Daniel Wong , Hongyu Qiu
Serum Response Factor (SRF) is a critical regulatory transcription factor widely expressed across cell types and is essential for animal survival. Excessive SRF activity has been linked to various pathological conditions and diseases, including cardiovascular diseases, cancers and neurodegenerative disorders, making the inhibition of SRF hyperactivity a promising therapeutic strategy. This review summarizes recent advancements in the discovery and development of SRF inhibitors, their regulatory mechanisms, and their respective molecular foundations. These insights deepen our understanding of current therapeutic potentials, paving the way for novel approaches to treat diseases associated with SRF hyperactivity.
{"title":"New insights into the pharmacological inhibition of SRF activity: Key inhibitory targets and mechanisms","authors":"Daniel Wong , Hongyu Qiu","doi":"10.1016/j.vph.2024.107443","DOIUrl":"10.1016/j.vph.2024.107443","url":null,"abstract":"<div><div>Serum Response Factor (SRF) is a critical regulatory transcription factor widely expressed across cell types and is essential for animal survival. Excessive SRF activity has been linked to various pathological conditions and diseases, including cardiovascular diseases, cancers and neurodegenerative disorders, making the inhibition of SRF hyperactivity a promising therapeutic strategy. This review summarizes recent advancements in the discovery and development of SRF inhibitors, their regulatory mechanisms, and their respective molecular foundations. These insights deepen our understanding of current therapeutic potentials, paving the way for novel approaches to treat diseases associated with SRF hyperactivity.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107443"},"PeriodicalIF":3.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717282","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}
Pub Date : 2024-11-19DOI: 10.1016/j.vph.2024.107442
Rosalinda Madonna, Filippo Biondi
Sotatercept (brand name WINREVAIR, developed by Merck) is an activin receptor type IIA-Fc (ActRIIA-Fc), working by sequestering free activins. Sotatercept restores the balance between the activin proliferative pathway and the bone morphogenic protein (BMP) antiproliferative pathway in the pulmonary arterial cirulation. Sotatercept recently received approval in the USA and in Europe for the treatment of adults with pulmonary arterial hypertension (PAH) Group 1, on top of background PAH therapy to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. Nevertheless, several studies are ongoing to investigate the potential adverse reactions of the drug especially at the haematological level. We provide an overview of the clinical and preclinical evidence of the targeting the activing pathway through sotatercept on the treatment of PAH. We also discuss what other possibilities there are for the application of sotatercept in the setting of pulmonary hypertension other than PAH Group 1.
{"title":"Sotatercept: New drug on the horizon of pulmonary hypertension","authors":"Rosalinda Madonna, Filippo Biondi","doi":"10.1016/j.vph.2024.107442","DOIUrl":"10.1016/j.vph.2024.107442","url":null,"abstract":"<div><div>Sotatercept (brand name WINREVAIR, developed by Merck) is an activin receptor type IIA-Fc (ActRIIA-Fc), working by sequestering free activins. Sotatercept restores the balance between the activin proliferative pathway and the bone morphogenic protein (BMP) antiproliferative pathway in the pulmonary arterial cirulation. Sotatercept recently received approval in the USA and in Europe for the treatment of adults with pulmonary arterial hypertension (PAH) Group 1, on top of background PAH therapy to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. Nevertheless, several studies are ongoing to investigate the potential adverse reactions of the drug especially at the haematological level. We provide an overview of the clinical and preclinical evidence of the targeting the activing pathway through sotatercept on the treatment of PAH. We also discuss what other possibilities there are for the application of sotatercept in the setting of pulmonary hypertension other than PAH Group 1.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107442"},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689032","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}
Pub Date : 2024-11-15DOI: 10.1016/j.vph.2024.107439
Yuan Chen , Yuan Li , Bin Leng , Chengrui Cao , Guifu Wu , Shugao Ye , Lin Deng
Background/objective
The pathogenesis and vascular remodeling during pulmonary hypertension (PH) have been associated with dysregulation of bone morphogenetic protein receptor type 2 (BMPR2) and transforming growth factor-β (TGF-β) signaling in pulmonary artery smooth muscle cells (PASMCs). Evidence suggests that the human-specific lncRNA MYOSLID is a transcriptional target of the TGF-β/SMAD pathway. In this study, we investigated the involvement of MYOSLID in the pathogenesis of PH.
Methods
Lung tissues from PH patients and rat PH models were analyzed to assess clinical relevance. RNA-Seq was performed to identify target genes. Pulmonary artery smooth muscle cells (PASMCs) were used to evaluate function and underlying mechanisms.
Results
RNA-Seq analysis of PASMCs stimulated by TGF-β1 revealed significantly dysregulated lncRNAs. MYOSLID expression was markedly elevated in lung tissues from PH patients and in PASMCs stimulated with TGF-β1. Mechanistically, loss of MYOSLID inhibited the TGF-β pathway by reducing SMAD2/3 PHosphorylation and activated the BMPR2 pathway by enhancing SMAD1/5/9 phosphorylation and increasing ID genes expression in PASMCs. DAZAP2, a target gene of MYOSLID, functions as an inhibitor of BMPR2 signaling. Moreover, DAZAP2 expression was significantly elevated in lung tissues from PH patients and rat PH models. Functionally, knockdown of MYOSLID and DAZAP2 reduced proliferation, migration, and apoptosis resistance in PASMCs.
Conclusion
The activation of the MYOSLID-DAZAP2-BMPR2 axis contributes to pulmonary vascular remodeling, and targeting MYOSLID and DAZAP2 may represent novel therapeutic strategies for PH treatment.
{"title":"LncRNA MYOSLID contributes to PH via targeting BMPR2 signaling in pulmonary artery smooth muscle cell","authors":"Yuan Chen , Yuan Li , Bin Leng , Chengrui Cao , Guifu Wu , Shugao Ye , Lin Deng","doi":"10.1016/j.vph.2024.107439","DOIUrl":"10.1016/j.vph.2024.107439","url":null,"abstract":"<div><h3>Background/objective</h3><div>The pathogenesis and vascular remodeling during pulmonary hypertension (PH) have been associated with dysregulation of bone morphogenetic protein receptor type 2 (BMPR2) and transforming growth factor-β (TGF-β) signaling in pulmonary artery smooth muscle cells (PASMCs). Evidence suggests that the human-specific lncRNA <em>MYOSLID</em> is a transcriptional target of the TGF-β/SMAD pathway. In this study, we investigated the involvement of <em>MYOSLID</em> in the pathogenesis of PH.</div></div><div><h3>Methods</h3><div>Lung tissues from PH patients and rat PH models were analyzed to assess clinical relevance. RNA-Seq was performed to identify target genes. Pulmonary artery smooth muscle cells (PASMCs) were used to evaluate function and underlying mechanisms.</div></div><div><h3>Results</h3><div>RNA-Seq analysis of PASMCs stimulated by TGF-β1 revealed significantly dysregulated lncRNAs. <em>MYOSLID</em> expression was markedly elevated in lung tissues from PH patients and in PASMCs stimulated with TGF-β1. Mechanistically, loss of <em>MYOSLID</em> inhibited the TGF-β pathway by reducing SMAD2/3 PHosphorylation and activated the BMPR2 pathway by enhancing SMAD1/5/9 phosphorylation and increasing ID genes expression in PASMCs. DAZAP2, a target gene of <em>MYOSLID</em>, functions as an inhibitor of BMPR2 signaling. Moreover, DAZAP2 expression was significantly elevated in lung tissues from PH patients and rat PH models. Functionally, knockdown of <em>MYOSLID</em> and DAZAP2 reduced proliferation, migration, and apoptosis resistance in PASMCs.</div></div><div><h3>Conclusion</h3><div>The activation of the <em>MYOSLID</em>-DAZAP2-BMPR2 axis contributes to pulmonary vascular remodeling, and targeting <em>MYOSLID</em> and DAZAP2 may represent novel therapeutic strategies for PH treatment.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107439"},"PeriodicalIF":3.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645052","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}
Pub Date : 2024-11-12DOI: 10.1016/j.vph.2024.107440
Natalya S. Zinkevich , Kostiantyn Drachuk , David X. Zhang
The Ca2+ ionophore A23187 induces endothelium-dependent and non-receptor-mediated vasodilation in human adipose arterioles (HAAs). The purpose of this study was to determine the mechanism of A23187-induced dilation in HAAs from patients with and without coronary artery disease (CAD). HAAs were freshly isolated from adipose tissues obtained from non-CAD (n = 25) and CAD (n = 14) patients, and vascular reactivity was studied by videomicroscopy. No difference in baseline dose response to A23187 was observed between non-CAD and CAD subjects. However, acute (30 min) incubation with N(omega)-nitro-l-arginine methyl ester (L-NAME), NO synthase inhibitor strongly reduced A23187-induced dilation in non-CAD arterioles, while catalase, an H2O2 scavenger, largely abolished dilation in CAD. Surprising, prolonged (90 min) incubation with L-NAME restored A23187 response in non-CAD subjects, which was subsequently inhibited by catalase. The action of prolonged L-NAME exposure was not reversible after washing with Krebs while the effect of acute L-NAME exposure was largely reversible. To further determine the role of mitochondria-derived ROS in A23187-induced dilation, arterioles were treated with rotenone, an inhibitor of complex I of the electron transport chain. Rotenone abolished A23187 response in CAD patients and in non-CAD arterioles after prolonged L-NAME, but not in non-CAD controls. These data indicate that NO contributes to A23187-induced dilation in HAAs from non-CAD patients and H2O2 contributes to the dilation in CAD patients. Prolonged L-NAME exposure induces a NO-H2O2 switch in the mechanism of dilation in non-CAD subjects. Moreover, the effect of prolonged L-NAME exposure is not readily reversible, while the action of acute L-NAME exposure is reversible.
{"title":"Prolonged L-NAME exposure changes the vasodilator factor from NO to H2O2 in human arterioles in response to A23187","authors":"Natalya S. Zinkevich , Kostiantyn Drachuk , David X. Zhang","doi":"10.1016/j.vph.2024.107440","DOIUrl":"10.1016/j.vph.2024.107440","url":null,"abstract":"<div><div>The Ca<sup>2+</sup> ionophore A23187 induces endothelium-dependent and non-receptor-mediated vasodilation in human adipose arterioles (HAAs). The purpose of this study was to determine the mechanism of A23187-induced dilation in HAAs from patients with and without coronary artery disease (CAD). HAAs were freshly isolated from adipose tissues obtained from non-CAD (<em>n</em> = 25) and CAD (<em>n</em> = 14) patients, and vascular reactivity was studied by videomicroscopy. No difference in baseline dose response to A23187 was observed between non-CAD and CAD subjects. However, acute (30 min) incubation with N(omega)-nitro-l-arginine methyl ester (L-NAME), NO synthase inhibitor strongly reduced A23187-induced dilation in non-CAD arterioles, while catalase, an H<sub>2</sub>O<sub>2</sub> scavenger, largely abolished dilation in CAD. Surprising, prolonged (90 min) incubation with L-NAME restored A23187 response in non-CAD subjects, which was subsequently inhibited by catalase. The action of prolonged L-NAME exposure was not reversible after washing with Krebs while the effect of acute L-NAME exposure was largely reversible. To further determine the role of mitochondria-derived ROS in A23187-induced dilation, arterioles were treated with rotenone, an inhibitor of complex I of the electron transport chain. Rotenone abolished A23187 response in CAD patients and in non-CAD arterioles after prolonged L-NAME, but not in non-CAD controls. These data indicate that NO contributes to A23187-induced dilation in HAAs from non-CAD patients and H<sub>2</sub>O<sub>2</sub> contributes to the dilation in CAD patients. Prolonged L-NAME exposure induces a NO-H<sub>2</sub>O<sub>2</sub> switch in the mechanism of dilation in non-CAD subjects. Moreover, the effect of prolonged L-NAME exposure is not readily reversible, while the action of acute L-NAME exposure is reversible.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"157 ","pages":"Article 107440"},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629271","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}
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