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...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 the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.展开更多
BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery re...BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme(ACE)2-angiotensin(Ang)(1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor(AT1)axis(ACE2/ACE axes)ratio on pulmonary artery lesion after return of spontaneous circulation(ROSC).METHODS:To establish a porcine massive APE with CA model,autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg(1 mmHg=0.133 kPa).Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation.Pigs were divided into four groups of five pigs each:control group,APE-CA group,ROSC-saline group,and ROSC-captopril group,to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril.RESULTS:Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells.Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor(VEGF)in the APE-CA group compared with the control group.Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC.Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X(Bax)ratio and decreasing cleaved caspase-3 expression.CONCLUSION:Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.展开更多
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...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.展开更多
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 ...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.展开更多
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...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.展开更多
基金supported by the National Natural Science Foundation of China (No. 81673858, No. 81704062, No. 30500644)the Science and Technology Project of Traditional Chinese Medicine in Hunan (No. 2009045, No. 2012027)the Program for National Center for Clinical Medicine for Geriatric Diseases (Ministry of Science and Technology)
文摘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 the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.
基金supported by grants from the National Natural Science Foundation of China(81773931 and 81374004)the Beijing Municipal Administration of Hospitals’Youth Program(QML20170105)+1 种基金the Natural Science Foundation of Beijing Municipality(7173253)the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support“Yangfan”Project(ZYLX201802)。
文摘BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme(ACE)2-angiotensin(Ang)(1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor(AT1)axis(ACE2/ACE axes)ratio on pulmonary artery lesion after return of spontaneous circulation(ROSC).METHODS:To establish a porcine massive APE with CA model,autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg(1 mmHg=0.133 kPa).Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation.Pigs were divided into four groups of five pigs each:control group,APE-CA group,ROSC-saline group,and ROSC-captopril group,to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril.RESULTS:Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells.Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor(VEGF)in the APE-CA group compared with the control group.Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC.Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X(Bax)ratio and decreasing cleaved caspase-3 expression.CONCLUSION:Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.
基金supported by National Natural Science Foundation of China (31571172 and 81870343 to Xiaoyong Tong,81700237 to Pingping Hu)Chongqing Natural Science Foundation (cstc2021jcyj-msxmX 0043 to Xiaoyong Tong,China)+1 种基金Chongqing Research Program of Basic Research and Frontier Technology (cstc2016jcyjA 0407 to Xiaoyong Tong,China)Fundamental Research Funds for the Central Universities (2018CDQYYX0042 to Xiaoyong Tong,and 2018CDYXYX0027 to Pingping Hu,China)。
文摘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.
基金funded by the China Scholarship Council(CSC)(no.202108080221)。
文摘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.
基金The work was supported by the Program of National Natural Science Foundation of China(81,700,045,82,000,059)the Three-year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals(SHDC2020CR4021)the Program of Shanghai Pulmonary Hospital(FKLY20005).
文摘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.
