Background: Restenosis (RS) poses a significant concern, leading to recurrent ischemia and the potential for amputation following intraluminal angioplasty in the treatment of Peripheral Artery Disease (PAD). Through microRNA microarray analysis, the study detected a significant downregulation of miR-199a-5p within arterial smooth muscle cells (ASMCs) associated with RS.
Objective: This research aims to explore the possible function and the underlying mechanisms of miR-199a-5p in the context of RS.
Methods: Primary ASMCs were extracted from the femoral arteries of both healthy individuals and patients with PAD or RS. The expression levels of miR-199a-5p were assessed using both qRT-PCR and in situ hybridization techniques. To examine the impacts of miR-199a-5p, a series of experiments were performed, including flow cytometry, TUNEL assay, EdU assay, CCK8 assay, Transwell assay, and wound closure assay. A rat carotid balloon injury model was employed to elucidate the mechanism through which miR-199a-5p mitigated neointimal hyperplasia.
Results: MiR-199a-5p exhibited downregulation in RS patients and was predominantly expressed within ASMCs. Elevated the expression of miR-199a-5p resulted in an inhibitory effect of proliferation and migration in ASMCs. Immunohistochemistry and a dual-luciferase reporter assay uncovered that RS exhibited elevated expression levels of both HIF-1α and E2F3, and they were identified as target genes regulated by miR-199a-5p. The co-transfection of lentiviruses carrying HIF-1α and E2F3 alongside miR-199a-5p further elucidated their role in the cellular responses mediated by miR-199a-5p. In vivo, the delivery of miR-199a-5p via lentivirus led to the mitigation of neointimal formation following angioplasty, achieved by targeting HIF-1α and E2F3.
Conclusion: MiR-199a-5p exhibits promise as a prospective therapeutic target for RS since it alleviates the condition by inhibiting the proliferation and migration of ASMCs via its regulation of HIF-1α and E2F3.
{"title":"MiR-199a-5p Deficiency Promotes Artery Restenosis in Peripheral Artery Disease by Regulating ASMCs Function via Targeting HIF-1α and E2F3.","authors":"Duan Liu, Yexiang Jing, Guiyan Peng, Litai Wei, Liang Zheng, Guangqi Chang, Mian Wang","doi":"10.2174/0115701611280634240616062413","DOIUrl":"https://doi.org/10.2174/0115701611280634240616062413","url":null,"abstract":"<p><strong>Background: </strong>Restenosis (RS) poses a significant concern, leading to recurrent ischemia and the potential for amputation following intraluminal angioplasty in the treatment of Peripheral Artery Disease (PAD). Through microRNA microarray analysis, the study detected a significant downregulation of miR-199a-5p within arterial smooth muscle cells (ASMCs) associated with RS.</p><p><strong>Objective: </strong>This research aims to explore the possible function and the underlying mechanisms of miR-199a-5p in the context of RS.</p><p><strong>Methods: </strong>Primary ASMCs were extracted from the femoral arteries of both healthy individuals and patients with PAD or RS. The expression levels of miR-199a-5p were assessed using both qRT-PCR and in situ hybridization techniques. To examine the impacts of miR-199a-5p, a series of experiments were performed, including flow cytometry, TUNEL assay, EdU assay, CCK8 assay, Transwell assay, and wound closure assay. A rat carotid balloon injury model was employed to elucidate the mechanism through which miR-199a-5p mitigated neointimal hyperplasia.</p><p><strong>Results: </strong>MiR-199a-5p exhibited downregulation in RS patients and was predominantly expressed within ASMCs. Elevated the expression of miR-199a-5p resulted in an inhibitory effect of proliferation and migration in ASMCs. Immunohistochemistry and a dual-luciferase reporter assay uncovered that RS exhibited elevated expression levels of both HIF-1α and E2F3, and they were identified as target genes regulated by miR-199a-5p. The co-transfection of lentiviruses carrying HIF-1α and E2F3 alongside miR-199a-5p further elucidated their role in the cellular responses mediated by miR-199a-5p. In vivo, the delivery of miR-199a-5p via lentivirus led to the mitigation of neointimal formation following angioplasty, achieved by targeting HIF-1α and E2F3.</p><p><strong>Conclusion: </strong>MiR-199a-5p exhibits promise as a prospective therapeutic target for RS since it alleviates the condition by inhibiting the proliferation and migration of ASMCs via its regulation of HIF-1α and E2F3.</p>","PeriodicalId":11278,"journal":{"name":"Current vascular pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442303","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 : 2024-06-20DOI: 10.2174/0115701611298073240612050741
Kevins Jara-Medina, Luis Lillo, Constanza Lagunas, Gerardo Cabello-Guzmán, Francisco J Valenzuela-Melgarejo
Background: Alzheimer's disease (AD) plays a prominent role as the most common form of dementia. Moreover, the traditional mechanism of AD does not explain the microvascular damage observed in about 25-30 years between the onset of AD, which results in late application treatment that inhibits or delays neurodegeneration.
Objective: Our objective was to identify differentially expressed genes in human brain samples associated with vascular disruption in AD.
Methods: We analyzed 1633 post-mortem brain samples in the GEO to database and, after applying clinical and bioinformatic exclusion criteria, worked with 581 prefrontal and frontal samples. All datasets were analyzed using GEO2R from NCBI. We identified common genes using the Venny tool, and their metabolic relevance associated with AD and the vascular system was analyzed using MetaboAnalyst tools.
Results: Our bioinformatic analysis identified PRKCB, MAP2K2, ADCY1, GNA11, GNAQ, PRKACB, KCNMB4, CALD1, and GNAS as potentially involved in AD pathogenesis. These genes are associated with signal transductions, cell death signaling, and cytoskeleton, suggesting potential modulation of cellular physiology, including endoplasmic reticulum and mitochondrial activity.
Conclusion: This study generates hypotheses regarding the roles of novel genes over critical pathways relevant to AD and its relation with vascular dysfunction. These findings suggest potential new targets for further investigation into the pathogenesis of dementia and AD.
背景:阿尔茨海默病(AD)是最常见的痴呆症。此外,传统的阿尔茨海默病发病机制无法解释阿尔茨海默病发病之间约 25-30 年间观察到的微血管损伤,这导致了抑制或延缓神经退行性变的晚期应用治疗:我们的目的是在人脑样本中找出与 AD 血管破坏相关的差异表达基因:我们分析了GEO数据库中的1633份死后脑部样本,在应用临床和生物信息学排除标准后,对581份前额叶和额叶样本进行了分析。所有数据集均使用 NCBI 的 GEO2R 进行分析。我们使用 Venny 工具确定了常见基因,并使用 MetaboAnalyst 工具分析了它们与 AD 和血管系统有关的代谢相关性:我们的生物信息学分析发现 PRKCB、MAP2K2、ADCY1、GNA11、GNAQ、PRKACB、KCNMB4、CALD1 和 GNAS 可能与 AD 发病机制有关。这些基因与信号转导、细胞死亡信号转导和细胞骨架有关,表明它们可能调节细胞生理机能,包括内质网和线粒体的活性:本研究提出了有关新基因在AD关键通路中的作用及其与血管功能障碍关系的假设。这些发现为进一步研究痴呆症和注意力缺失症的发病机制提供了潜在的新靶点。
{"title":"Identification of Vascular Genes Differentially Expressed in the Brain of Patients with Alzheimer's Disease.","authors":"Kevins Jara-Medina, Luis Lillo, Constanza Lagunas, Gerardo Cabello-Guzmán, Francisco J Valenzuela-Melgarejo","doi":"10.2174/0115701611298073240612050741","DOIUrl":"https://doi.org/10.2174/0115701611298073240612050741","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) plays a prominent role as the most common form of dementia. Moreover, the traditional mechanism of AD does not explain the microvascular damage observed in about 25-30 years between the onset of AD, which results in late application treatment that inhibits or delays neurodegeneration.</p><p><strong>Objective: </strong>Our objective was to identify differentially expressed genes in human brain samples associated with vascular disruption in AD.</p><p><strong>Methods: </strong>We analyzed 1633 post-mortem brain samples in the GEO to database and, after applying clinical and bioinformatic exclusion criteria, worked with 581 prefrontal and frontal samples. All datasets were analyzed using GEO2R from NCBI. We identified common genes using the Venny tool, and their metabolic relevance associated with AD and the vascular system was analyzed using MetaboAnalyst tools.</p><p><strong>Results: </strong>Our bioinformatic analysis identified PRKCB, MAP2K2, ADCY1, GNA11, GNAQ, PRKACB, KCNMB4, CALD1, and GNAS as potentially involved in AD pathogenesis. These genes are associated with signal transductions, cell death signaling, and cytoskeleton, suggesting potential modulation of cellular physiology, including endoplasmic reticulum and mitochondrial activity.</p><p><strong>Conclusion: </strong>This study generates hypotheses regarding the roles of novel genes over critical pathways relevant to AD and its relation with vascular dysfunction. These findings suggest potential new targets for further investigation into the pathogenesis of dementia and AD.</p>","PeriodicalId":11278,"journal":{"name":"Current vascular pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442302","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 : 2024-06-13DOI: 10.2174/0115701611299843240607061547
Fahime Shokrollahi, Ali Pazoki, Abbas Allami, Shahin Aliakbari, Kimia Rahimi Ardali
Introduction/objective: Coronavirus disease 2019 (COVID-19) has been the biggest pandemic in history, with severe complications, such as acute respiratory distress syndrome and pulmonary hypertension (PH). An endothelin-1 (ET-1) receptor antagonist, such as bosentan, may be beneficial in treating elevated ET-1 levels. Hence, our study aimed to evaluate the therapeutic effects of bosentan in patients with COVID-19-induced PH.
Methods: A single-centre, randomized, double-blind study involving 72 participants was carried out; 36 received bosentan and the other 36 received a placebo. Pulmonary arterial pressure, tricuspid valve pressure gradient, and right atrial pressure were measured using echocardiography. The Cox proportional hazards regression model was used to investigate the impact of bosentan and patients' age on mortality during a 6-month follow-up period.
Results: In-hospital mortality was significantly lower in the case group (13%) compared with the control group (33.3%) (P=0.003). Additionally, bosentan improved echocardiographic parameters, such as systolic pulmonary artery pressure and tricuspid regurgitation gradient (P=0.011 and P=0.003, respectively). Bosentan use was a significant predictor of long-term mortality rates for 600 days [age-adjusted hazard ratio of 5.24 (95% CI 1.34 to 20.46)].
Conclusion: This study provided a mixed perspective on the use of bosentan therapy in patients with COVID-19-related PH. Bosentan effectively reduced in-hospital mortality and improved echocardiographic measures. However, the treatment group showed an increased requirement for supplemental oxygen therapy and long-term mortality. Further studies with larger sample sizes are necessary to elucidate the effects of bosentan in PH following COVID-19.
{"title":"Bosentan and Pulmonary Hypertension Caused by COVID-19: A Pilot Randomized Double-blind Clinical Study.","authors":"Fahime Shokrollahi, Ali Pazoki, Abbas Allami, Shahin Aliakbari, Kimia Rahimi Ardali","doi":"10.2174/0115701611299843240607061547","DOIUrl":"https://doi.org/10.2174/0115701611299843240607061547","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Coronavirus disease 2019 (COVID-19) has been the biggest pandemic in history, with severe complications, such as acute respiratory distress syndrome and pulmonary hypertension (PH). An endothelin-1 (ET-1) receptor antagonist, such as bosentan, may be beneficial in treating elevated ET-1 levels. Hence, our study aimed to evaluate the therapeutic effects of bosentan in patients with COVID-19-induced PH.</p><p><strong>Methods: </strong>A single-centre, randomized, double-blind study involving 72 participants was carried out; 36 received bosentan and the other 36 received a placebo. Pulmonary arterial pressure, tricuspid valve pressure gradient, and right atrial pressure were measured using echocardiography. The Cox proportional hazards regression model was used to investigate the impact of bosentan and patients' age on mortality during a 6-month follow-up period.</p><p><strong>Results: </strong>In-hospital mortality was significantly lower in the case group (13%) compared with the control group (33.3%) (P=0.003). Additionally, bosentan improved echocardiographic parameters, such as systolic pulmonary artery pressure and tricuspid regurgitation gradient (P=0.011 and P=0.003, respectively). Bosentan use was a significant predictor of long-term mortality rates for 600 days [age-adjusted hazard ratio of 5.24 (95% CI 1.34 to 20.46)].</p><p><strong>Conclusion: </strong>This study provided a mixed perspective on the use of bosentan therapy in patients with COVID-19-related PH. Bosentan effectively reduced in-hospital mortality and improved echocardiographic measures. However, the treatment group showed an increased requirement for supplemental oxygen therapy and long-term mortality. Further studies with larger sample sizes are necessary to elucidate the effects of bosentan in PH following COVID-19.</p>","PeriodicalId":11278,"journal":{"name":"Current vascular pharmacology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317031","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}
Permanent pacemakers are an established treatment for sick sinus syndrome and high-grade atrioventricular block. Permanent cardiac pacemaker implantations may damage the myocardium. This study evaluated markers of myocardial injury, oxidative stress and inflammation in elderly patients with permanent pacemaker implantations Various markers were measured at 1, 2, 3 and 4 months after permanent pacemaker implantations in elderly patients. The levels of high-sensitivity troponin T (hsTnT), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), malondialdehyde-modified low-density lipoprotein (MDA-LDL), oxidized low-density lipoprotein (OX-LDL), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) were increased in 2-month group compared with control and 1- month groups (P<0.001), and were further increased at 4-month group compared with 2- and 3- month groups after pacemaker implantations (P<0.001). Patients with dual-chamber pacemakers had higher levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB than patients with single chamber pacemakers (P<0.001). Patients who underwent the pacemakers with the active fixation leads had raised levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB compared patients with pacemakers using the passive fixation leads (P<0.001). Myocardial blood flows in 3-month and 4-month groups were lower than 1-month and 2-month groups (P<0.001). Levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB were elevated in elderly patients with permanent pacemaker implantations and the activations of oxidative stress and pro-inflammatory signalling pathways may be associated with myocardial damages and ischemia after pacemaker implantations in elderly patients.
{"title":"Roles of MDA-LDL/OX-LDL/LOX-1 and TNF-α/TLR4/NF-κB Signaling\u0000Pathways in Myocardial Damage by Implantations of Cardiac Pacemakers\u0000in Elderly Patients","authors":"Xia Li, Wenhang Zhou, Dianxuan Guo, Y. Hu, Hualan Zhou, Ying Chen","doi":"10.2174/0115701611260215231221072709","DOIUrl":"https://doi.org/10.2174/0115701611260215231221072709","url":null,"abstract":"\u0000\u0000Permanent pacemakers are an established treatment for sick sinus syndrome\u0000and high-grade atrioventricular block. Permanent cardiac pacemaker implantations may damage the\u0000myocardium.\u0000\u0000\u0000\u0000This study evaluated markers of myocardial injury, oxidative stress and inflammation in\u0000elderly patients with permanent pacemaker implantations\u0000\u0000\u0000\u0000Various markers were measured at 1, 2, 3 and 4 months after permanent pacemaker implantations\u0000in elderly patients.\u0000\u0000\u0000\u0000The levels of high-sensitivity troponin T (hsTnT), lectin-like oxidized low-density lipoprotein\u0000receptor-1 (LOX-1), malondialdehyde-modified low-density lipoprotein (MDA-LDL), oxidized\u0000low-density lipoprotein (OX-LDL), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4)\u0000and nuclear factor-kappa B (NF-κB) were increased in 2-month group compared with control and 1-\u0000month groups (P<0.001), and were further increased at 4-month group compared with 2- and 3-\u0000month groups after pacemaker implantations (P<0.001). Patients with dual-chamber pacemakers had\u0000higher levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB than patients with\u0000single chamber pacemakers (P<0.001). Patients who underwent the pacemakers with the active fixation\u0000leads had raised levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB\u0000compared patients with pacemakers using the passive fixation leads (P<0.001). Myocardial blood\u0000flows in 3-month and 4-month groups were lower than 1-month and 2-month groups (P<0.001).\u0000\u0000\u0000\u0000Levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB were elevated\u0000in elderly patients with permanent pacemaker implantations and the activations of oxidative\u0000stress and pro-inflammatory signalling pathways may be associated with myocardial damages and\u0000ischemia after pacemaker implantations in elderly patients.\u0000","PeriodicalId":11278,"journal":{"name":"Current vascular pharmacology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141351124","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}