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GRK2-YAP signaling is implicated in pulmonary arterial hypertension development

中华医学杂志(英文版) 2024年第7期137卷 846-858页

作者： Ye Peng Deng Yunfei Gu Yue Liu Pengfei Luo Jie Pu Jiangqin Chen Jingyu Huang Yu Wang Nanping Ji Yong Chen Shaoliang Wuxi People’s Hospital Wuxi Jiangsu 300247 Institute of Vascular Medicine The Chinese University of Hong Kong Hongkong 999077 Health Science Center East China Normal University Shanghai 200241 School of Pharmacy Division of Cardiovascular Molecular Laboratory Jiangsu 210004 Third Clinical College Nanjing Medical University Nanjing Jiangsu 210006 China Division of Cardiovascular Laboratory Nanjing First Hospital Division of pulmonary Surgery

Background: pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown.Methods: GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specificGrk2-knockout mice (Grk2?SM22), and littermate controls (Grk2flox/flox) were grouped into control and hypoxia mice (n = 8). pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels ofGrk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays.Results: The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated inGrk2?SM22 mice compared with littermate controls. The amelioration of PH inGrk2?SM22 mice was accompanied by reduced pulmonary vascular remodeling.In vitro study further confirmed thatGRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression ofGRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferat

关键词： pulmonary arterial hypertension GRK2 YAP pulmonary artery smooth muscle cell Hypoxia

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Potential impact of specific therapy on pregnant women with pulmonary arterial hypertension without cardiac shunt:a descriptive study in northern China

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Emergency and Critical Care Medicine 2024年第2期4卷 60-66页

作者： Weida Lu Min Li Fuqing Ji Hua Feng Guo Li Qiushang Ji Hongyu Zhang Xiaopei Cui Department of Geriatric Medicine&Shandong Key Laboratory Cardiovascular Proteomics Qilu Hospital of Shandong UniversityJinanShandongChina Intensive Care Unit of Cardiac Surgery Shandong Provincial Qianfoshan Hospitalthe First Hospital Affiliated with Shandong First Medical UniversityAffiliated Hospital of Shandong UniversityJinanShandongChina Department of Cardiology Linyi Central HospitalLinyiShandongChina Department of Gastroenterology Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongChina Department of pulmonary and Critical Care Medicine the Affiliated Hospital of Qingdao UniversityQingdaoShandongChina Department of Cardiology Qilu Hospital of Shandong UniversityJinanShandongChina

Background:Pregnancy in women with pulmonary arterial hypertension(PAH)is a fatal condition,despite the effectiveness of PAH-specific therapies.The coverage status and effect of specific therapies in pregnant patients with PAH without cardiac shunts in China remain unclear.To investigate this issue,we conducted a multicenter retrospective study in northern China.Methods:The study included 85 patients who were admitted to 4 clinical centers in Shandong Province between October 2010 and August 2020.Maternal endpoint events included(1)maternal death and/or(2)major adverse cardiac events,both occurring during pregnancy or within 6 weeks postpartum.Results:Although the overall mortality rate was encouraging(11.8%),the number of patients receiving PAH-specific therapies was extremely low(28.2%).Moreover,only 15.3%of patients received adequate duration of PAH-specific therapy(≥4 weeks)before delivery,and this subgroup showed the lowest major adverse cardiac events rate(7.7%)compared with that in the untreated(19.7%)and short-time treated groups(<4 weeks;54.5%).Conclusion:Pregnant patients with PAH without cardiac shunts face significantly increased mortality risks.Short-term PAH-specific therapy does not guarantee favorable maternal outcomes.Prepregnancy screening,early identification,and timely intervention are expected to improve maternal outcomes in pregnant women with PAH.

关键词： Major adverse cardiac events Maternal mortality Pregnancy outcome pulmonary arterial hypertension Specific therapy

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Mufangji tang ameliorates pulmonary arterial hypertension through improving vascular remodeling,inhibiting inflammatory response and oxidative stress,and inducing apoptosis

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Traditional Medicine Research 2024年第2期9卷 52-65页

作者： Yu-Ming Wang Hong-Wei Tao Feng-Chan Wang Ping Han Na Liu Guo-Jing Zhao Hai-Bo Hu Xue-Chao Lu College of Traditional Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China Department of Respiratory and Critical Care Medicine Qingdao Hospital of Traditional Chinese Medicine(Qingdao Hiser hospital)Qingdao 266000China.

Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disorders,notably including pulmonary arterial hypertension(PAH).However,the mechanism of action of MFJT on PAH remains unknown.Methods:In this study,a monocrotaline-induced PAH rat model was established and treated with MFJT.The therapeutic effects of MFJT on PAH rat model were evaluated.Network pharmacology was conducted to screen the possible targets for MFJT on PAH,and the molecular docking between the main active components and the core targets was carried out.The key targets identified from network pharmacology were tested.Results:Results showed significant therapeutic effects of MFJT on PAH rat model.Analysis of network pharmacology revealed several potential targets related to apoptosis,inflammation,oxidative stress,and vascular remodeling.Molecular docking showed that the key components were well docked with the core targets.Further experimental validation results that MFJT treatment induced apoptosis(downregulated Bcl-2 levels and upregulated Bax levels in lung tissue),inhibited inflammatory response and oxdative stress(decreased the levels of IL-1β,TNF-α,inducible NOS,and malondialdehyde,and increased the levels of endothelial nitric oxide synthase,nitric oxide,glutathione and superoxide dismutase),reduced the proliferation of pulmonary arterial smooth muscle cells(downregulated ET-1 andβ-catenin levels and ERK1/2 phosphorylation,increased GSK3βlevels).Conclusion:Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis,inhibition of inflammation and oxidative stress,and the prevention of vascular remodeling.

关键词： Mufangji tang pulmonary arterial hypertension apoptosis inflammatory response oxidative stress vascular remodeling

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NOTCH3 Mutations and CADASIL Phenotype in pulmonary arterial hypertension Associated with Congenital Heart Disease

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Congenital Heart Disease 2022年第6期17卷 675-686页

作者： Rui Jiang Kaisheng Lai Jianping Xu Xiang Feng Shaoye Wang Xiaojian Wang Zhe Liu Department of Adult Cardiac Surgery National Center for Cardiovascular DiseasesFuwai HospitalChinese Academy of Medical SciencesPeking Union Medical CollegeBeijingChina BestNovo(Beijing)Medical Laboratory BeijingChina Key Laboratory of pulmonary Vascular Medicine Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Background:The etiology of pulmonary arterial hypertension associated with congenital heart disease(PAHCHD)is complicated and the phenotype is heterogeneous.Genetic defects of NOTCH3 were associated withcerebral disease and pulmonary hypertension.However,the relationship between NOTCH3 mutations and theclinical phenotype has not been reported in CHD-PAH.Methods:We eventually enrolled 142 PAH-CHD patientsfrom Fuwai Hospital.Whole exome sequencing(WES)was performed to screen the rare deleterious variants ofNOTCH3 gene.Results:This PAH-CHD cohort included 43(30.3%)men and 99(69.7%)women with the meanage 29.8±10.9 years old.The pathogenic or likely pathogenic mutations of NOTCH3 were identified in five cases.Patients 2,5,8 and 11 carried the same NOTCH3 mutation c.1630C>T(pArg544Cys),which is the hot-spotmutation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL).Patient 3 carried the NOTCH3 mutation p.Arg75Gln that has also been reported to be associatedwith the CADASIL.Patients 2,5,8,11 took the examination of the cerebral magnetic resonance imaging(MRI)and confirmed the phenotype of CADASIL.Conclusions:We first reported the NOTCH3 rare mutationsand CADASIL phenotypes in CHD-PAH patients.The NOTCH3 rare variants were with a relatively high positiverate and CADASIL phenotypes were likely enriched in PAH-CHD patients.The preoperative neurological examinationmight be recommended for PAH-CHD patients to determine the surgical contraindications and reduceintraoperative neurological complications.

关键词： pulmonary arterial hypertension Congenital heart disease NOTCH3 Cerebral autosomal dominant arteriopathy with subcortical infarcts and lesions(CADASIL)

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pulmonary arterial hypertension confirmed by right heart catheterization following COVID-19 pneumonia: A case report and review of literature

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World Journal of Respirology 2023年第1期12卷 10-15页

作者： Marshaleen Henriques King Ifeoma Chiamaka Ogbuka Vincent C Bond Department of pulmonary and Critical Care Morehouse School of MedicineAtlantaGA 30310United States Hospital Medicine Covenant HealthKnoxvilleTN 37922United States Department of Microbiology Biochemistry&ImmunologyMorehouse School of MedicineAtlantaGA 30310United States

BACKGROUND pulmonary arterial hypertension(PAH)is a disease of the arterioles resulting in an increased resistance in pulmonary circulation with associated high pressures in the pulmonary arteries,causing irreversible remodeling of the pulmonary arterial walls.Coronavirus disease 2019(COVID-19)has been associated with development of new onset PAH in the literature leading to symptoms of dyspnea,cough and fatigue that persist in spite of resolution of acute COVID-19 infection.However,the majority of these cases of COVID related PAH were diagnosed using echocardiographic data or via right heart catheterization in mechanically ventilated patients.CASE SUMMARY Our case is the first reported case of COVID related PAH diagnosed by right heart catheterization in a non-mechanically ventilated patient.Right heart catheterization has been the gold standard for diagnosis of pulmonary hypertension.Our patient had right heart catheterization four months after her initial COVID-19 infection due to persistent dyspnea.CONCLUSION This revealed new onset PAH that developed following her infection with COVID-19,an emerging sequela of the infection.

关键词： pulmonary arterial hypertension post COVID-19 infection PAH after COVID-19 infection COVID-19 induced pulmonary arterial hypertension diagnosed with right heart catheterization pulmonary arterial hypertension pulmonary arterial hypertension Right heart catheterization Right heart catheterization COVID-19

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Rutaecarpine attenuates monocrotaline-induced pulmonary arterial hypertension in a Sprague-Dawley rat model

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Traditional Medicine Research 2023年第1期8卷 26-35页

作者： Xiao-Wei Gong Yan-Ling Sheng Shi-Wei Kang Bo-Yun Yuan Ya-Dong Yuan Department of Respiratory and Critical Care Medicine The Second Hospital of Hebei Medical UniversityShijiazhuang 050000China Department of Respiratory and Critical Care Medicine Huabei Petroleum Administration Bureau General HospitalRenqiu 062550China.

Background:pulmonary arterial hypertension presents with obliterative remodeling of the pulmonary arteries and progressive elevation of pulmonary vascular resistance,which increase the risk of right ventricular failure and death.It has been reported in previous studies that rutaecarpine plays a crucial role in anti-inflammatory and antioxidant activities,which may help regulate cell apoptosis and cell proliferation.The purpose of this study was to determine the effects of rutaecarpine in the rat model of monocrotaline-induced pulmonary hypertension.Methods:We induced pulmonary arterial hypertension in adult Sprague-Dawley rats by injecting monocrotaline(60 mg/kg)and then treated with rutaecarpine(40 mg/kg·d)or sildenafil(30 mg/kg·d)(positive control).Subsequently,pulmonary function,inflammation,cytokines and pulmonary vascular remodeling or proliferation were assessed.Results:Rutaecarpine was found to improve monocrotaline-induced mean pulmonary artery pressure,cardiac index,right heart index,right ventricular hypertrophy index,pulmonary artery remodeling and pulmonary function.reverse transcription-quantitative polymerase chain reaction demonstrated a decrease in tumor necrosis factor-α,interleukin-6 and interleukin-1β,whereas western blots a significantly decrease in the expression of nuclear factor kappa-B,endothelin-1,extracellular signal-regulated kinases 1/2,B cell lymphoma-2,Beclin1 and microtubule-associated protein1 light chain 3-II protein,and increase in the expression of Bax,caspase-3 and p62 protein.Conclusion:Rutaecarpine attenuated pulmonary arterial hypertension by inhibiting inflammation,oxidative stress,cell proliferation and autophagy,while promoting apoptosis.

关键词： rutaecarpine pulmonary arterial hypertension inflammatory response oxidative stress vascular proliferation

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Bioinformatics Analysis of the Regulatory lncRNA–miRNA–mRNA Network and Drug Prediction in Patients with pulmonary arterial hypertension

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Cardiology Discovery 2023年第2期3卷 85-94页

作者： Xiao Jin Ling Jin Li Han Shiping Zhu Department of Traditional Chinese Medicine The First Affiliated Hospital of Jinan UniversityGuangzhouGuangdong 510630China.

Objective:pulmonary arterial hypertension(PAH)is a cardiovascular disease caused by primary proliferative lesions in pulmonary arterioles.Competing endogenous RNAs(ceRNAs)have been reported to act as sponges for microRNAs(miRNAs).To date,however,the mechanisms underlying ceRNA involvement in PAH have not been investigated.This study aimed to construct a PAH-related ceRNA network to further explore the mechanisms of PAH.Methods:A probe reannotation was conducted to identify the long non-coding RNAs(lncRNAs)and messenger RNAs(mRNAs)involved in PAH.Based on the reannotation results,the“limma”package was used to identify the differentially expressed genes(DEGs)and lncRNAs.The miRcode database was used to predict the lncRNA–miRNA interactions.Then,the mRNAs targeted by the miRNAs were predicted by using TargetScan,miRTarBase,and miRDB.Based on the above interactions,a ceRNA network was constructed,which was mapped and visualized with Cytoscape 3.6.1 software.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the database.To predict possible drugs or molecules that may mitigate PAH,C-Map analysis was applied to find relevant molecular compounds that can reverse the expression of DEGs in cell lines.Results:The ceRNA network consisted of 174 nodes and 304 links,which included 10 lncRNAs,23 miRNAs,and 53 mRNAs.The hub genes of the ceRNA network for PAH included hsa-miR-17-5p,hsa-miR-20b-5p,MEG3,HCP5,hsa-miR-27a-3p,hsa-miR-107,hsa-miR-142-3p,hsa-miR-363-3p,hsa-miR-301b-3p,and hsa-miR-23b-3p.Calprotectin,irinotecan,and medrysone were found to be the 3 significant compounds.Conclusion:This study found that hsa-miR-17-5p,hsa-miR-20b-5p,MEG3,HCP5,hsa-miR-27a-3p,hsa-miR-107,hsa-miR-142-3p,hsa-miR-363-3p,hsa-miR-301b-3p,and hsa-miR-23b-3p maybe the underlying biomarkers and targets for diagnosis and treatment of PAH.

关键词： pulmonary arterial hypertension Competing endogenous RNAs Bioinformatics analysis

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A Network Meta-analysis of the Efficacy and Safety of Targeted Drug Combinations in the Treatment of pulmonary arterial hypertension

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Cardiology Discovery 2023年第4期3卷 249-260页

作者： Rui Wang Meng Wei Jie Wang Xiang Huang Qianzhi Yan Shichao Wang Yun Wu Department of General Medicine The First Affiliated Hospital of Xinjiang Medical UniversityUrumqiXinjiang 830011China Department of Pharmacy The First Affiliated Hospital of Xinjiang Medical UniversityUrumqiXinjiang 830011China Pacing and Electrophysiological Division The First Affiliated Hospital of Xinjiang Medical UniversityUrumqiXinjiang 830011China

Objective:This network meta-analysis aims to compare the efficacy and safety of different targeted drug combination treatment for pulmonary arterial hypertension(PAH).Methods:Searches were conducted in Cochrane,PubMed,EMBASE,China National Knowledge Infrastructure,China Biomedical Literature Database,Wanfang Database,and ViP Chinese Science and Technology Journal Data to identify both published and unpublished randomized controlled trials from inception until January 1,2022.The risk of bias in the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions.A network metaanalysis was performed using Stata 16.0 software.The efficacy and safety of different targeted drugs combined treatment for PAH were evaluated based on forest plot,funnel plot,and surface under the cumulative ranking.Results:A total of 29 randomized controlled trails with 4,448 patients treated with 10 different types of targeted drug combinations were included in this study.The results of the surface under the cumulative ranking showed that the combination regimen was the best clinical option to improve symptoms and delay progression in patients with pulmonary artery hypertension compared with monotherapy.Sildenafil in combination with ambrisentan significantly improved the 6-minute walk distance and reduced N-terminal pro-brain natriuretic peptide levels.Bosentan in combination with sildenafil significantly reduced mean pulmonary artery pressure,whereas bosentan in combination with epoprostenol was more effective than other combinations in reducing pulmonary vascular resistance.Bosentan in combination with tadalafil significantly improved the Borg dyspnea score,and bosentan in combination with iloprost was the best combination for improving World Health Organization functional class/New York Heart Association functional class.In terms of safety,there was no significant reduction in the incidence of adverse events,hospitalizations,or allcause mortality for combination therapy compared with monoth

关键词： Meta-analysis pulmonary arterial hypertension Targeted drug Treatment

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Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

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Acta Pharmaceutica Sinica B 2020年第12期10卷 2339-2347页

作者： Yuncong Yangy Sirui Zhangy Qian Zhouy Chen Zhang Yuqi Gao Hao Wang Zhe Li Deyan Wu Yinuo Wu Yi-You Huang Lei Guo Hai-Bin Luo School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH treatment.The crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.

关键词： Phosphodiesterase 10A Inhibitor Benzimidazole derivatives Crystal structure Metabolic stability Bioavailability pulmonary arterial hypertension

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Treatment with neurohormonal inhibitors and prognostic outcome in pulmonary arterial hypertension with risk factors for left heart disease

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World Journal of Critical Care Medicine 2022年第2期11卷 85-91页

作者： Riccardo Scagliola Claudio Brunelli Manrico Balbi Cardiovascular Disease Unit IRCCS Ospedale Policlinico San MartinoGenova 16132GenovaItaly

BACKGROUND Despite major advances in pharmacologic treatment,patients with pulmonary arterial hypertension(PAH)still have a considerably reduced life expectancy.In this context,chronic hyperactivity of the neurohormonal axis has been shown to be detrimental in PAH,thus providing novel insights on the role of neurohormonal blockade as a potential therapeutic target.AIM To evaluate the application and prognostic effect of neurohormonal inhibitors(NEUi)in a single-center sample of patients with idiopathic PAH and risk factors for left heart disease.METHODS We analyzed data retrospectively collected from our register of right heart catheterizations performed consecutively from January 1,2005 to October 31,2018.Patients on beta-blocker,angiotensin-converting enzyme inhibitor,angiotensin receptor blocker or mineralocorticoid receptor antagonist at the time of right heart catheterization were classified as NEUi users and compared to NEUi nonrecipients.RESULTS Complete data were available for 57 PAH subjects:27 of those(47.4%)were taking at least one NEUi at the time of right heart catheterization and were compared with the remaining 36 NEUi non-recipients.NEUi users were older and had a higher cardiovascular risk profile compared to non-recipients.Additionally,NEUi non-users had a higher probability of dying during the course of follow-up than NEUi recipients(56.7%vs 25.9%,log-rank P=0.020).CONCLUSION The above data highlighted a subgroup of patients with PAH and comorbidities for left heart disease in which NEUi use has shown to be associated with improved survival.Future prospective studies are needed to identify the most appropriate therapeutic strategies in this subset population.

关键词： pulmonary arterial hypertension Left heart disease Neurohormonal inhibitors Prognostic outcome Right heart catheterization Pharmacological treatment

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