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The substitution of SERCA2 redox cysteine 674 promotes pulmonary vascular remodeling by activating IRE1α/XBP1s pathway

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2315-2329页

作者： Weimin Yu Gang Xu Hui Chen Li Xiao Gang Liu Pingping Hu Siqi Li Vivi Kasim Chunyu Zeng Xiaoyong Tong School of Pharmaceutical Sciences Chongqing UniversityChongqing 401331China Institute of Health Biological Chemical Medication Chongqing Institute of Green and Intelligent TechnologyChinese Academy of SciencesChongqing 400714China Institute of Medicine and Equipment for High Altitude Region College of High Altitude Military MedicineArmy Medical University(Third Military Medical University)Chongqing 400038China Key Laboratory of High Altitude Medicine People’s Liberation ArmyChongqing 400038China Henan Key Laboratory of Medical Tissue Regeneration College of Basic Medical SciencesXinxiang Medical UniversityXinxiang 453003China Key Laboratory of Biorheological Science and Technology Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400044China Department of Cardiology Daping HospitalArmy Medical University(Third Military Medical University)Chongqing 400042China

pulmonary hypertension(PH) is a life-threatening disease characterized by pulmonary vascular remodeling, in which hyperproliferation of pulmonary artery smooth muscle cells(PASMCs)plays an important role. The cysteine 674(C674) in the sarcoplasmic/endoplasmic reticulum Ca^(2+)ATPase 2(SERCA2) is the critical redox regulatory cysteine to regulate SERCA2 activity. Heterozygous SERCA2 C674 S knock-in mice(SKI), where one copy of C674 was substituted by serine to represent partial C674 oxidative inactivation, developed significant pulmonary vascular remodeling resembling human PH, and their right ventricular systolic pressure modestly increased with age. In PASMCs, substitution of C674 activated inositol requiring enzyme 1 alpha(IRE1 a) and spliced X-box binding protein 1(XBP1 s) pathway, accelerated cell cycle and cell proliferation, which reversed by IRE1 a/XBP1 s pathway inhibitor 4μ8 C. In addition, suppressing the IRE1 a/XBP1 s pathway prevented pulmonary vascular remodeling caused by substitution of C674. Similar to SERCA2 a, SERCA2 b is also important to restrict the proliferation of PASMCs. Our study articulates the causal effect of C674 oxidative inactivation on the development of pulmonary vascular remodeling and PH, emphasizing the importance of C674 in restricting PASMC proliferation to maintain pulmonary vascular homeostasis. Moreover, the IRE1 a/XBP1 s pathway and SERCA2 might be potential targets for PH therapy.

关键词： pulmonary hypertension Sarcoplasmic/endoplasmic reticulum Ca^(2+)ATPase pulmonary vascular remodeling pulmonary artery smooth muscle cell Endoplasmic reticulum stress Oxidative stress

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Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics

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Journal of Geriatric Cardiology 2019年第12期16卷 855-871页

作者： Xi CHEN Jia-Mei YAO Xia FANG Cui ZHANG Yu-Shu YANG Cheng-Ping HU Qiong CHEN Guang-Wei ZHONG National Center for Clinical Medicine for Geriatric Diseases Xiangya HospitalCentral South UniversityChangshaChina Department of Respiratory Medicine Xiangya HospitalCentral South UniversityChangshaChina Department of Geriatrics Xiangya HospitalCentral South UniversityChangshaChina International Medical Center Xiangya HospitalCentral South UniversityChangshaChina

Background Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension(PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance. However, the molecular mechanism underlying of this balance is still unknown. Methods To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1α(HIF-1α) on pulmonary arterial smooth muscle cell(PASMC) and pulmonary arterial hypertension rats, the cells were cultured in a hypoxic chamber under oxygen concentrations. Cell viability, reactive oxygen species level, cell death, mitochondrial morphology, mitochondrial membrane potential, mitochondrial function and mitochondrial biosynthesis, as well as fission-and fusion-related proteins, were measured under hypoxic conditions. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure, right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded. Further, we assessed the role of HIF-1α in the development and progression of PH using HIF-1α gene knockdown using small interfering RNA transfection. Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1(Drp1). Results We found that HIF-1α expression was increased during hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis. We also found that targeting mitochondrial fission Drp1 by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats. The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro. Furthermore, HIF-1α also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp1. Conclusions In conclusion, our data suggests that abnormal mitochondrial dynamics could be a marker for

关键词： Dynamin-related protein 1 Hypoxia Hypoxia-inducible factor-1α Mitochondrial dynamics pulmonary vascular remodeling

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Effects of low ambient temperatures and dietary vitamin C supplementation on pulmonary vascular remodeling and hypoxic gene expression of 21-d-old broilers

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Journal of Integrative Agriculture 2016年第1期15卷 183-190页

作者： ZENG Qiu-feng YANG Xia ZHENG Ping ZHANG Ke-ying LUO Yu-heng DING Xue-mei BAI Shi-ping WANG Jian-ping XUAN Yue SU Zhuo-wei Key Laboratory for Animal Disease Resistance Nutrition Ministry of EducationInstitute of Animal Nutrition Sichuan Agricultural University

The objective of this study was to evaluate the effects of low ambient temperature （LAT） and dietary vitamin C （VC） sup- plementation on pulmonary vascular remodeling （PVR） and the relative expression of hypoxia inducible factor-la （HIF-la）, vascular endothelial growth factor （VEGF） and its receptor 2 （VEGFR-2） mRNA of lungs in 21-d-old broilers. 400 1-d-old male Cobb broilers were assigned randomly to 4 treatments as follows for 21 d： 1 ） LAT and a basal diet; 2） LAT and a basal diet supplemented with 1 000 mg kg-1 VC （LAT＋VC）; 3） normal ambient temperature （NAT） and a basal diet; 4） NAT and a basal diet supplemented with 1 000 mg kg-1 VC （NAT＋VC）. Each treatment was composed of 10 replicates of 10 birds per replicate. Samples of lung were collected after the broilers were killed at d 21. LAT increased the ratio of vessel wall area to vessel total area （WA/TA, %） and mean media thickness in pulmonary arterioles （mMTPA, %）（P〈0.05）. Dietary VC supplementation decreased mMTPA （P〈0.05）, but had no effect on the WA/TA. LAT increased （P〈0.05） the relative mRNA expression of HIF-la, VEGF and VEGFR-2, while adding VC to the diet could decrease （P〈0.05） their relative mRNA expression. A significant positive correlation existed between the level of VEGF mRNA expression and the value of WA/WT （P〈0.05） or mMTPA （P〈0.05）. These results suggested LAT resulted in pulmonary vascular remodeling, and the increase of HIF-la, VEGF and VEGFR-2 mRNA expression, and dietary VC supplementation can alleviate pulmonary vascular remodeling in broiler by affecting these gene expression.

关键词： broiler hypoxia inducible factor-la low ambient temperature pulmonary vascular remodeling vitamin C

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The Role of Endogenous Carbon Monoxide in the Hypoxic vascular remodeling of Rat Model of Hypoxic pulmonary Hypertension

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第4期23卷 356-358,368页

作者：甄国华张珍祥徐永健 Department of pulmonary Medicine

We investigated the expression of heme oxygenase 1 (HO 1) gene and production of endogenous carbon monoxide (CO) in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin on the expression of HO 1 gene and pulmonary hypertension. A rat model of hypoxic pulmonary hypertension was recreated by exposure to intermittent normobaric hypoxic environment (10 % O 2). Reverse transcriptase polymerase chain reaction (RT PCR) was performed to determine the level of HO 1 mRNA in the rat lung tissue and double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood. Cardiac catheterization was employed to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathological changes of the intra acinar pulmonary arteries (IAPA). It was found that (1) There was a low level of HO 1 mRNA in normal rat lung tissue, but the level of HO 1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats ( P pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.

关键词： heme oxygenase hypoxia pulmonary hypertension pulmonary vascular remodeling

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The key role of micro RNAs in mitochondria fusion protein 1 mediated pulmonary vascular remodeling

The key role of micro RNAs in mitochondria fusion protein 1 ...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者： Cui Ma Chen Zhang Hongmin Yao Yumei Liu Lixin Zhang Mingfei Ma Daling Zhu 哈尔滨医科大学大庆校区 Department of Biopharmaceutical Sciences College of PharmacyHarbin Medical University-Daqing

AIM:The imbalance of pulmonary arterial smooth muscle cells（PASMCs）mitochondrial homeostasis induced abnormal proliferation is an important pathological process in the hypoxic pulmonary arterial hypertension,the molecular mechanism is unknown.We hypothesis that hypoxia affect the form and functions of mitochondria,regulate the cell cycle progression,increase the cell proliferation and pulmonary vascular remodeling.METHODS:We prove this hypothesis by the following research:1).we performed animal models,cell biology and molecular biology to determine the mitochondrial function in pathogenesis of pulmonary arterial hypertension and clarify the role of mitochondria fusion protein（Mfn1）in hypoxia induced PASMCs proliferation.2)By bioinformatics we explore the role of mi RNAs in hypoxia regulated Mfn1 expression and determining the key mi RNA.3)By overexpression or knock down mi RNAs,to determine the regulation of mi RNAs in PASMCs mitochondrial fusion process.4)To test the effects of mi RNA on the different phases of cell cycle progression,PASMCs were performed the analyses of the cell cycle profiles,the cyclins expression after overexpression or knock down mi RNAs were also detected.RESULTS:We found that hypoxia changed morphological of mitochondrial into vacuoles and swelling,and increased the mitochondrial fission process.Mfn1 was increased in hypoxia and monocrotaline induced pulmonary vascular remodeling.We also found that hypoxia induced smooth muscle cells proliferation in a Mfn1 dependent manner.Furthermore,bioinformatics results showed that Mfn1 was mediated by mi R-125 and mi R-351.Subsequently,we studied the function of these mi RNAs in PASMC apoptosis under hypoxic conditions.The promotive effect of Mfn1 was weakened in the presence of mi R-125 and mi R-351 mimics.CONCLUSION:In the present study we determined the role of mi RNAs in regulating mitochondria fusion protein expression in hypoxia by bioinformatics for the the first time.These results provide a theoretical basis for the prevention and treatment

关键词： hypoxia pulmonary vascular remodeling pulmonary arterial smooth muscle cells mitochondria fusion protein 1 micro RNAs

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ROCK Pathway Participates in the Processes that 15-Hydroxyeicosatetraenoic Acid(15-HETE)Mediated the pulmonary vascular remodeling Induced by Hypoxia in Rat

ROCK Pathway Participates in the Processes that 15-Hydroxyei...

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中国药理学会第十次全国学术会议

作者：马俊哈尔滨医科大学药学院

15-Hydroxyeicosatetraenoic acid(15-HETE),a product of arachidonic acid(AA) catalyzed by 15-lipoxygenase (15-LO),plays an essential role in hypoxic pulmonary arterial hypertension.We have previously shown that 15-HETE inhibits apoptosis in pulmonary artery smooth muscle cells(PASMCs).To test the hypothesis that such an effect is attributable to the hypoxia-induced pulmonary vascular remodeling(PVR),we performed these studies in which we found subtle thickening of proximal media/adventitia of the pulmonary arteries(PA) in the rats that had been exposed to hypoxia.This was associated with up-regulation of the anti-apoptotic Bcl-2 expression and down-regulation of pro-apoptotic caspase-3 and Bax expressions in PA homogenates.Nordihydroguaiaretic acid (NDGA),an endogenous 15-HETE inhibitor,reversed all the alterations.In situ hybridization histochemistry and immunocytochemistry showed that the 15-LO-1 mRNA and protein were localized in PA endothelial cells(PAECs), while the 15-LO-2 mRNA and protein were localized in both PAECs and PASMCs.Furthermore,the Rho-kinase (ROCK) pathway was activated by both endogenous and exogenous 15-HETE,alleviating the serum deprivation-induced PASMC apoptosis.Thus,these findings indicate that 15-HETE protects PASMC from apoptosis,contributing to pulmonary vascular medial thickening,and the effect is,at least in part,mediated via the ROCK pathway.

关键词： 15-hydroxyeicosatetraenoic acid pulmonary vascular remodeling Rho-kinase apoptosis hypoxia

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Role of LOX-1 in pulmonary vascular remodeling in rats with hypoxia induced pulmonary arterial hypertension and the underlying mechanisms

Role of LOX-1 in pulmonary vascular remodeling in rats with ...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者： Weifang ZHANG Changping HU 中南大学 Department of Pharmacology School of Pharmaceutical SciencesCentral South University

Aim:To investigate the role of lectin-like oxidized low-density lipoprotein receptor-1（LOX-1）in pulmonary vascular remodeling in rats with hypoxia-induced pulmonary arterial hypertension（PAH）and the underlying mechanisms.Methods:SD rats were maintained under hypoxia（10%O2）for 3 weeks to induce PAH.The right ventricular systolic pressure（RVSP）,the mean pulmonary arterial pressure（m PAP）were monitored.Excised lungs were fixed to observe pulmonary vascular remodeling.Rat pulmonary arterial smooth muscle cells（PASMCs）were stimulated by 3%O2 to induce cell proliferation.Theexpression of LOX-1,p Elk,MRTF-A,SRF,c-fos was analyzed.Results:Exposure of rats to hypoxia for 3weeks induced PAH,as shown as by an increase in RVSP,m PAP and vascular hypertrophy.The expression of LOX-1,p Elk,SRF,c-fos was significantly increased while MRTF-A is decreased in pulmonary artery in hypoxia-induced PAH rats and in hypoxia-treated PASMCs.Anti-LOX-1 antibody and LOX-1 si RNA significantly inhibited hypoxia-induced proliferation of PASMCs,and reversed the increased expression of p Elk,SRF and c-fos as well as the decreased MRTF-A expression in hypoxia-treated PASMCs.Conclusion:LOX-1 is a novel regulator of hypoxia-induced proliferation of PASMCs via p Elk/MRTF-A/SRF/c-fos pathway,which may contribute to pulmonary vascular remodeling in rats with hypoxia-induced PAH.

关键词： pulmonary arterial hypertension pulmonary vascular remodeling lectin-like oxidized low density lipoprotein receptor-1

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Animal models of pulmonary hypertension due to left heart disease

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Animal Models and Experimental Medicine 2022年第3期5卷 197-206页

作者： Shao-Fei Liu Yi Yan Charité-Universitätsmedizin Berlin Corporate Member of Freie Universität BerlinHumboldt-Universität zu Berlinand Berlin Institute of HealthBerlinGermany DZHK(German Centre for Cardiovascular Research) Partner Site BerlinBerlinGermany Institute for Cardiovascular Prevention(IPEK) Ludwig-Maximilians-University MunichMunichGermany DZHK(German Centre for Cardiovascular Research) Partner Site Munich Heart AllianceMunichGermany

pulmonary hypertension due to left heart disease(PH-LHD) is regarded as the most prevalent form of pulmonary hypertension(PH). Indeed, PH is an independent risk factor and predicts adverse prognosis for patients with left heart disease(LHD). Clinically, there are no drugs or treatments that directly address PH-LHD, and treatment of LHD alone will not also ameliorate PH. To target the underlying physiopathological alterations of PH-LHD and to develop novel therapeutic approaches for this population, animal models that simulate the pathophysiology of PH-LHD are required. There are several available models for PH-LHD that have been successfully employed in rodents or large animals by artificially provoking an elevated pressure load on the left heart, which by transduction elicits an escalated pressure in pulmonary artery. In addition, metabolic derangement combined with aortic banding or vascular endothelial growth factor receptor antagonist is also currently applied to reproduce the phenotype of PH-LHD. As of today, none of the animal models exactly recapitulates the condition of patients with PH-LHD. Nevertheless, the selection of an appropriate animal model is essential in basic and translational studies of PH-LHD. Therefore, this review will summarize the characteristics of each PH-LHD animal model and discuss the advantages and limitations of the different models.

关键词： animal model l eft ventricular failure metabolic syndrome pulmonary hypertension due to left heart disease pulmonary vascular remodeling

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The effect of rehabilitation exercise on the expression of glutaminase and cardiopulmonary remodeling in pulmonary hypertension

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Medicine in Novel Technology and Devices 2022年第3期15卷 134-143页

作者： Shang Wang Ping Yuan Yuan-Yuan Sun Yi Yan Yu-Xia Huang Xiao-Yi Hu Lan Wang Kuan Cheng Rong Jiang Department of Cardio-pulmonary Circulation Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China Heart Center and Shanghai Institute of Pediatric Congenital Heart Disease Shanghai Children's Medical CenterNational Children's Medical CenterShanghai Jiaotong University School of MedicineShanghaiChina Institute for Cardiovascular Prevention(IPEK) Ludwig Maximilian University MunichMunichGermany Department of Cardiology Zhongshan HospitalFudan UniversityShanghai Institute of Cardiovascular DiseasesShanghai200032China

pulmonary hypertension(PH)is featured by pulmonary vascular and cardiac remodeling.Rehabilitation exercise can improve patients’quality of life.We previously pinpointed a potential glutamine metabolism dysfunction in PH.Hence,we aim to investigate whether rehabilitation exercise could mitigate right ventricular and pulmonary vascular remodeling and its effect on glutaminase(GLS).We collected clinical indicators of PH patients and analyzed their correlation with GLS.Rehabilitation exercise(moderate intensity swimming exercise)was performed in monocrotaline-induced PH(MCT-PH)rats.We found that plasma GLS1 level in patients was lower than healthy subjects,and it was negatively correlated with end-systolic stage eccentricity index,right atrial transverse dimension and right atrial longitudinal dimension.MCT-PH rats displayed pulmonary vascular remodeling and right ventricular hypertrophy.Compared to control rats,higher levels of GLS1 and GLS2 mRNA in lung and lower levels of these two isoforms of GLS in right ventricle(RV)were displayed in MCT-PH rats.After swimming exercise,GLS mRNA levels in the lung and RV were significantly upregulated,and the cross-sectional area of right ventricular cardiomyocytes was significantly decreased although the percentage of pulmonary arteriolar medial wall thickness was not significantly changed.Therefore,we hold the opinion that plasma GLS1 level was decreased in PH.The transcriptional levels of GLS1 and GLS2 were increased in the lung tissues in PH,but were decreased in the RV tissues.Meanwhile,the changes of GLS levels indicated the pulmonary vascular and right ventricular remodeling.Whereas moderate intensity swimming exercise might improve the right ventricular remodeling by regulating the levels of GLS.

关键词： pulmonary hypertension pulmonary vascular remodeling Cardiac remodeling Glutaminase

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