Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease with a complex pathogenesis. It is often associated with an increased vascular resistance, whilst in the more advanced stages there is a remodelling of the vascular walls. PAH has an intricate involvement of various signaling pathways, including the ras homolog family member A (RhoA)–Rho kinase (ROCK) axis. Currently, available therapies are not always able to significantly slow PAH progression. Therefore, newer approaches are needed.

Areas covered: In this review, areas covered include the role of the RhoA/ROCK in PAH pathogenesis and the plausibility of its therapeutic targeting. Furthermore, various inhibitory compounds are discussed, including Fasudil and SB-772077-B.

Expert opinion: Currently, specific RhoA/ROCK inhibition is the most promising therapeutic approach for PAH. Research has shown that it suppresses both the components of this axis and the upstream upregulating mediators. An inhaled RhoA/ROCK inhibitor may be a successful future therapy; however, further clinical trials are needed to support this approach.     

盐酸法舒地尔对PCI术后慢血流冠心病患者内皮细胞损伤的作用及其机制研究*

目的 探讨采用盐酸法舒地尔治疗对减轻经皮冠脉介入术（PCI）后慢血流冠状动脉粥样硬化性心脏病（以下简称冠心病）患者血管内皮细胞损伤的临床价值。方法 选取2015年5月—2016年8月华北石油管理局总医院实施PCI治疗慢血流冠心病患者120例作为研究对象。按入院顺序随机分为治疗组和对照组,每组 60例。两组患者术后均采用常规治疗,治疗组术后同时给予盐酸法舒地尔治疗,疗程2周。对比两组的血管内皮损伤、内皮舒张及炎症指标。治疗后随访3个月,记录两组患者发生的心血管不良事件。结果 治疗前两组患者外周血内皮细胞微粒（EMPs）、血管性假血友病因子（vWF）、内皮素-1（ET-1）、一氧化氮NO、一氧化氮合酶（eNOS）、血管舒张功能（FMD）、血管内皮舒张功能（NMD）、白细胞介素-6（IL-6）、C反应蛋白（CRP）及肿瘤细胞坏死因子-α（TNF-α）比较,差异无统计学意义（P?>0.05）;治疗后两组患者上述指标比较,差异 有统计学意义（P?<0.05）,治疗组EMPs、vWF、ET-1、IL-6、CRP和TNF-α降低,NO、eNOS、FMD及NMD 升高;治疗前后两组比较,治疗后患者外周血EMPs、vWF、ET-1、IL-6、CRP及TNF-α较治疗前降低（P?<0.05）,NO、eNOS、FMD及NMD较治疗前升高（P?<0.05）;与对照组比较,治疗组治疗后的心血管不良事件发生降低 （P?<0.05）。结论 冠心病PCI术后采用盐酸法舒地尔治疗能减轻慢血流冠心病患者的炎症反应程度及血管内皮细胞损伤。     

盐酸法舒地尔对脑梗死患者的疗效及对血清中lL-1β、TNF-α和RHO激酶影响的观察

目的:本实验观察盐酸法舒地尔对脑梗死患者的治疗作用及对血清中白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)和RHO激酶的影响,为临床工作提供理论帮助.方法:选取我院住院诊治的脑梗死患者186例,依患者的入院顺序分为两组,观察组共93例,在常规治疗基础上加用盐酸法舒地尔治疗,对照组共93例,只应用常规治疗...     

盐酸法舒地尔联合奥扎格雷钠治疗短暂性脑缺血发作30例

目的观察盐酸法舒地尔联合奥扎格雷钠对短暂性脑缺血发作的临床疗效和安全性。方法将60例短暂性脑缺血发作患者随机均分为两组,治疗组用盐酸法舒地尔30 mg静脉滴注,12 h滴完,奥扎格雷钠80 mg静脉滴注,12 h滴完,均连用14 d;对照组单用奥扎格雷钠80 mg静脉滴注,12 h滴完,连用14 d。观察两组临床疗效和不良反应,检测血常规、尿常规、肝功能、肾功能以及凝血指标。结果两组基本痊愈率比较差异有统计学意义(P<0.05),总显效率比较差异无统计学意义(P>0.05);治疗组短暂性脑缺血发作停止时间早于对照组。两组均无明显不良反应,血常规、尿常规、肝功能、肾功能以及凝血指标无明显改变。结论盐酸法舒地尔联合奥扎格雷钠治疗短暂性脑缺血发作不但能够提高疗效,而且安全,可以考虑将其试用于短暂性脑缺血发作的治疗。     

Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis

Aim:

Fasudil, a selective Rho kinase (ROCK) inhibitor, has been shown to alleviate the severity of experimental autoimmune encephalomyelitis (EAE) via attenuating demyelination and neuroinflammation. The aim of this study was to investigate the effects of fasudil on interactions between macrophages/microglia and T cells in a mice EAE model.

Methods:

Mouse BV-2 microglia were treated with IFN-γ and fasudil. Cell viability was detected with MTT assay. BV-2 microglia polarization was analyzed using flow cytometry. Cytokines and other proteins were detected with ELISA and Western blotting, respectively. Mice were immunized with MOG_35–55 to induce EAE, and then treated with fasudil (40 mg/kg, ip) every other day from d 3 to d 27 pi. Encephalomyelitic T cells were prepared from the spleen of mice immunized with MOG_35–55 on d 9 pi.

Results:

Treatment of mouse BV-2 microglia with fasudil (15 μg/mL) induced significant phenotype polarization and functional plasticity, shifting M1 to M2 polarization. When co-cultured with the encephalomyelitic T cells, fasudil-treated BV-2 microglia significantly inhibited the proliferation of antigen-reactive T cells, and down-regulated IL-17-expressing CD4⁺ T cells and IL-17 production. Furthermore, fasudil-treated BV-2 microglia significantly up-regulated CD4⁺CD25^high and CD4⁺IL-10⁺ regulatory T cells (Tregs) and IL-10 production, suggesting that the encephalomyelitic T cells had converted to Tregs. In EAE mice, fasudil administration significantly decreased both CD11b⁺iNOS⁺ and CD11b⁺TNF-α⁺ M1 microglia, and increased CD11b⁺IL-10⁺ M2 microglia.

Conclusion:

Fasudil polarizes BV-2 microglia into M2 cells, which convert the encephalomyelitic T cells into Tregs in the mice EAE model.     

盐酸法舒地尔后适应对大鼠心肌缺血再灌注损伤的保护作用

目的通过主动脉根部模拟冠状动脉内给药,观察盐酸法舒地尔后适应对大鼠急性心肌缺血再灌注损伤的保护作用。方法选择SD大鼠48只,随机分为假手术组、缺血再灌注组、缺血后适应组、法舒地尔组,每组12只。各组于再灌注3 h后处死大鼠,分别测定心功能参数、血浆心肌酶、心肌梗死范围和心肌细胞凋亡指数。结果与假手术组比较,缺血再灌注组、缺血后适应组和法舒地尔组血浆心肌酶含量明显升高,差异有统计学意义(P<0.01)。与缺血再灌注组比较,法舒地尔组心功能参数明显改善,血浆心肌酶含量、心肌梗死范围、心肌细胞凋亡指数明显下降,差异有统计学意义(P<0.01)。结论盐酸法舒地尔可以模拟缺血后适应效应,减轻心肌缺血再灌注损伤,减少缺血心肌细胞凋亡,缩小心肌梗死范围。     

法舒地尔治疗老年慢性充血性心力衰竭临床疗效观察

目的观察法舒地尔治疗老年充血性心力衰竭的临床疗效。方法选取就诊于我院老年医学科充血性心力衰竭患者90例。根据随机分组原则分为对照组、治疗组。对照组患者使用常规抗心衰药物治疗：治疗组患者在对照组基础上联合法舒地尔60mg静脉滴注,1次／d,2周为1个疗程,每月1个疗程,连续3月。观察2组患者治疗后临床症状、治疗总有效率、血清脑钠肽（BNP）、左室射血分数等指标变化。结果治疗组治疗总有效率为95．6％,显著高于对照组的82．2％（P〈0．05）;治疗后治疗组患者血清BNP、左室射血分数改善情况显著优于对照组（P〈0．05）。结论使用法舒地尔治疗老年充血性心力衰竭能够有效改善心功能,且安全性高。     

法舒地尔动、静脉给药治疗颅内动脉瘤栓塞后脑血管痉挛的对比研究

目的探讨法舒地尔动脉推注(IAF)与静脉给药对脑动脉瘤栓塞后脑血管痉挛(CVS)的疗效对比并评估其安全性。方法介入栓塞治疗后出现脑血管痉挛39名患者,随机分成A、B二组。A组,改用静脉法舒地尔治疗,30 mg,3次/d;B组立即行动脉内注射盐酸法舒地尔(60 mg+生理盐水100 ml,60 min缓慢推注治疗),连续3 d,3 d后予常规静脉法舒地尔治疗。结果 B组IAF治疗后血管痉挛程度明显改善,第3 d、7 d、14 d的GCS评分均高于A组,3月后GOS评分明显高于A组。结论 IAF能安全有效地缓解蛛网膜下腔出血后脑血管痉挛的临床症状并改善预后。