Publications
100 results found
Abdul-Salam V, Russomanno G, Chien-Nien C, et al., 2019, CLIC4/Arf6 pathway – a new lead in BMPRII inhibition in pulmonary hypertension, Circulation Research, Vol: 124, Pages: 52-65, ISSN: 0009-7330
Rationale:Increased expression of CLIC4 (chloride intracellular channel 4) is a feature of endothelial dysfunction in pulmonary arterial hypertension, but its role in disease pathology is not fully understood.Objective:To identify CLIC4 effectors and evaluate strategies targeting CLIC4 signaling in pulmonary hypertension.Methods and Results:Proteomic analysis of CLIC4-interacting proteins in human pulmonary artery endothelial cells identified regulators of endosomal trafficking, including Arf6 (ADP ribosylation factor 6) GTPase activating proteins and clathrin, while CLIC4 overexpression affected protein regulators of vesicular trafficking, lysosomal function, and inflammation. CLIC4 reduced BMPRII (bone morphogenetic protein receptor II) expression and signaling as a result of Arf6-mediated reduction in gyrating clathrin and increased lysosomal targeting of the receptor. BMPRII expression was restored by Arf6 siRNA, Arf inhibitor Sec7 inhibitor H3 (SecinH3), and inhibitors of clathrin-mediated endocytosis but was unaffected by chloride channel inhibitor, indanyloxyacetic acid 94 or Arf1 siRNA. The effects of CLIC4 on NF-κB (nuclear factor-kappa B), HIF (hypoxia-inducible factor), and angiogenic response were prevented by Arf6 siRNA and SecinH3. Sugen/hypoxia mice and monocrotaline rats showed elevated expression of CLIC4, activation of Arf6 and NF-κB, and reduced expression of BMPRII in the lung. These changes were established early during disease development. Lung endothelium–targeted delivery of CLIC4 siRNA or treatment with SecinH3 attenuated the disease, reduced CLIC4/Arf activation, and restored BMPRII expression in the lung. Endothelial colony–forming cells from idiopathic pulmonary hypertensive patients showed upregulation of CLIC4 expression and Arf6 activity, suggesting potential importance of this pathway in the human condition.Conclusions:Arf6 is a novel effector of CLIC4 and a new therapeutic target in pulmonary hypertension.
Ashek A, Spruijt OA, Harms HJ, et al., 2018, 3 '-deoxy-3'-[18F]fluorothymidine positron emission tomography depicts heterogeneous proliferation pathology in idiopathic pulmonary arterial hypertension patient lung: a potential biomarker for pulmonary arterial hypertension, Circulation: Cardiovascular Imaging, Vol: 11, ISSN: 1941-9651
Background:Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodeling in pulmonary arterial hypertension. A noninvasive imaging biomarker is needed to track the pathology and assess the response to novel treatments targeted at resolving the structural changes. Here, we evaluated the application of radioligand 3′-deoxy-3′-[18F]-fluorothymidine (18FLT) using positron emission tomography.Methods and Results:We performed dynamic 18FLT positron emission tomography in 8 patients with idiopathic pulmonary arterial hypertension (IPAH) and applied in-depth kinetic analysis with a reversible 2-compartment 4k model. Our results show significantly increased lung 18FLT phosphorylation (k3) in patients with IPAH compared with nonpulmonary arterial hypertension controls (0.086±0.034 versus 0.054±0.009 min−1; P<0.05). There was heterogeneity in the lung 18FLT signal both between patients with IPAH and within the lungs of each patient, compatible with histopathologic reports of lungs from patients with IPAH. Consistent with 18FLT positron emission tomographic data, TK1 (thymidine kinase 1) expression was evident in the remodeled vessels in IPAH patient lung. In addition, hyperproliferative pulmonary vascular fibroblasts isolated from patients with IPAH exhibited upregulated expression of TK1 and the thymidine transporter, ENT1 (equilibrative nucleoside transporter 1). In the monocrotaline and SuHx (Sugen hypoxia) rat pulmonary arterial hypertension models, increased lung 18FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation marker, Ki-67 score, together with prominent TK1 expression in remodeled vessels. Importantly, lung 18FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib.Conclusions:Dynamic 18FLT positron emission tomography imaging can be used to report hyperproliferation in pulmonary h
Michelakis ED, Gurtu V, Webster L, et al., 2017, Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients, Science Translational Medicine, Vol: 9, Pages: 1-13, ISSN: 1946-6234
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
Todd Milne G, on behalf of the Ironwood team, Sandner P, et al., 2017, Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications : Bamberg, Germany. 23-25 June, 2017.
Rudyk O, Krasemann S, Hartmann K, et al., 2017, PKGI alpha oxidation during chronic hypoxia provides an adaptive vasodilatory mechanism that limits pulmonary hypertension, 34th European Section of the International Society for Heart Research, Publisher: ELSEVIER SCI LTD, Pages: 9-9, ISSN: 0022-2828
Duluc L, Ahmetaj-Shala B, Mitchell J, et al., 2017, Tipifarnib prevents development of hypoxia-induced pulmonary hypertension, Cardiovascular Research, Vol: 113, Pages: 276-287, ISSN: 1755-3245
Aims.RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and Results.The analysis of lung tissues from rodent models and pulmonary hypertensive patientsshowed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerisation and increased eNOS expression in vitroand in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB) and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator.Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins.Conclusions.Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodeling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
Ashek A, Dubois O, Wilkins M, et al., 2016, Kinetic Analysis Of 3 '-Deoxy-3 '-[18f]-Fluorothymidine (flt) Positron Emission Tomography (pet) In Monocrotaline-Induced Pulmonary Hypertension Rat, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Zhao L, Oliver E, Maratou K, et al., 2015, The zinc transporter, ZIP12, regulates the pulmonary vascular response to chronic hypoxia, Nature, Vol: 524, Pages: 356-360, ISSN: 0028-0836
The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1, 2, 3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
Zhao L, 2015, Iron homeostasis and pulmonary hypertension: iron deficiency leads to pulmonary vascular remodelling in the rat, Circulation Research, Vol: 116, Pages: 1680-1690, ISSN: 1524-4571
Rationale: Iron deficiency without anemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival.Objectives: We hypothesized that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy.Methods and Results: Rats were fed an iron-deficient diet (IDD, 7 mg/kg) and investigated for 4 weeks. Iron deficiency was evident from depleted iron stores (decreased liver, serum iron, and ferritin), reduced erythropoiesis, and significantly decreased transferrin saturation and lung iron stores after 2 weeks IDD. IDD rats exhibited profound pulmonary vascular remodeling with prominent muscularization, medial hypertrophy, and perivascular inflammatory cell infiltration, associated with raised pulmonary artery pressure and right ventricular hypertrophy. IDD rat lungs demonstrated increased expression of hypoxia-induced factor-1α and hypoxia-induced factor-2α, nuclear factor of activated T cells and survivin, and signal transducers and activators of transcription-3 activation, which promote vascular cell proliferation and resistance to apoptosis. Biochemical examination showed reduced mitochondrial complex I activity and mitochondrial membrane hyperpolarization in mitochondria from IDD rat pulmonary arteries. Along with upregulation of the glucose transporter, glucose transporter 1, and glycolytic genes, hk1 and pdk1, lung fluorine-18–labeled 2-fluoro-2-deoxyglucose ligand uptake was significantly increased in IDD rats. The hemodynamic and pulmonary vascular remodeling were reversed by iron replacement (ferric carboxymaltose, 75 mg/kg) and attenuated in the presence of iron deficiency by dichloroacetate and imatinib, 2 putative treatments explored for pulmonary arterial hypertension that target aerobic glycolysis and proliferation, respectively.Conclusions: These data suggest a major role for iron in pulmonary vascular
Wilkins MR, Ghofrani H-A, Weissmann N, et al., 2015, Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease, CIRCULATION, Vol: 131, Pages: 582-590, ISSN: 0009-7322
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- Citations: 85
Ashek A, Tang SP, Dubois O, et al., 2014, Quantification of respiratory inflammation with [11C]PBR28 in a rodent model of pulmonary arterial hypertension, Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S389-S389, ISSN: 1619-7070
Francis BN, Hale A, Channon KM, et al., 2014, Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat, PULMONARY CIRCULATION, Vol: 4, Pages: 462-470, ISSN: 2045-8932
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- Citations: 16
Iannone L, Zhao L, Dubois O, et al., 2014, <i>miR</i>-<i>21</i>/DDAH1 pathway regulates pulmonary vascular responses to hypoxia, BIOCHEMICAL JOURNAL, Vol: 462, Pages: 103-112, ISSN: 0264-6021
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- Citations: 42
Wojciak-Stothard B, Abdul-Salam VB, Lao KH, et al., 2014, Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension, Circulation, Vol: 129, Pages: 1770-1780, ISSN: 0009-7322
Background—Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodeled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension. CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of pulmonary arterial hypertension.Methods and Results—CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, whereas CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension attenuated the abnormal angiogenic behavior that characterizes these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-κB, followed by stabilization of hypoxia-inducible factor-1α and increased downstream production of vascular endothelial growth factor and endothelin-1.Conclusion—Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.
George PM, Oliver E, Dorfmuller P, et al., 2014, Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension, CIRCULATION RESEARCH, Vol: 114, Pages: 677-688, ISSN: 0009-7330
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- Citations: 98
Iannone L, Leiper J, Zhao L, et al., 2014, Ddah1 Regulates Pulmonary Vascular Responses To Hypoxia Via Mir-21, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
Cotroneo E, Ashek A, Wharton J, et al., 2014, Pulmonary Vascular Remodelling In The Chronic Iron-Deficient Rat, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
Watson G, Oliver E, Zhao L, et al., 2013, Pulmonary hypertension: Old targets revisited (Statins, PPARs, Beta-Blockers), Handbook of Experimental Pharmacology, Vol: 218, Pages: 531-548, ISSN: 0171-2004
Pulmonary arterial hypertension is a therapeutic challenge. Despite progress in recent years with three drug classes-prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors-long-term patient survival remains poor. Importantly, the introduction and commercial success of these new treatments has been accompanied by growing interest in the pathology of pulmonary hypertension. This, in turn, has stimulated a re-evaluation of the molecular factors driving the structural remodelling of pulmonary arterioles and the opportunities to preserve right ventricular function in pulmonary hypertension. Academics with restricted access to new chemicals have turned to existing drugs to investigate new ideas. It is in this context that the role of statins, peroxisome proliferator-activated receptors (PPARs) and beta-blockers are of interest as potential treatments for pulmonary hypertension. © Springer-Verlag Berlin Heidelberg 2013.
Wang L, Guo L-J, Liu J, et al., 2013, MicroRNA expression profile of pulmonary artery smooth muscle cells and the effect of let-7d in chronic thromboembolic pulmonary hypertension, PULMONARY CIRCULATION, Vol: 3, Pages: 654-664, ISSN: 2045-8932
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- Citations: 26
Li J-F, Lin Y, Yang Y-H, et al., 2013, Fibrinogen Aα Thr312Ala Polymorphism Specifically Contributes to Chronic Thromboembolic Pulmonary Hypertension by Increasing Fibrin Resistance, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 24
Zhao L, Ashek A, Wang L, et al., 2013, Heterogeneity in lung 18FDG uptake in PAH: potential of dynamic 18FDG-PET with kinetic analysis as a bridging biomarker for pulmonary remodeling targeted treatments, Circulation
Zhao L, Chen C-N, Hajji N, et al., 2013, Response to Letter Regarding Article, "Histone Deacetylation Inhibition in Pulmonary Hypertension: Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid", CIRCULATION, Vol: 127, Pages: E540-E540, ISSN: 0009-7322
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- Citations: 4
Chen C-N, Watson G, Zhao L, 2013, Cyclic guanosine monophosphate signalling pathway in pulmonary arterial hypertension, VASCULAR PHARMACOLOGY, Vol: 58, Pages: 211-218, ISSN: 1537-1891
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- Citations: 12
Ashek A, Dubois O, Gsell W, et al., 2013, Assessment Of Vascular Remodelling In Pulmonary Arterial Hypertension In Vivo Using 18f-Flurodeoxyglucose Positron Emission Tomography (pet) Imaging, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
Watson G, Oliver E, Zhao L, et al., 2013, Pulmonary Hypertension: Old Targets Revisited (Statins, PPARs, Beta-Blockers), PHARMACOTHERAPY OF PULMONARY HYPERTENSION, Editors: Humbert, Evgenov, Stasch, Publisher: SPRINGER-VERLAG BERLIN, Pages: 531-548, ISBN: 978-3-642-38664-0
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- Citations: 7
Hameed AG, Arnold ND, Chamberlain J, et al., 2012, Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 209, Pages: 1919-1935, ISSN: 0022-1007
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- Citations: 71
Zhao L, Chen C-N, Hajji N, et al., 2012, Histone Deacetylation Inhibition in Pulmonary Hypertension Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid, CIRCULATION, Vol: 126, Pages: 455-+, ISSN: 0009-7322
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- Citations: 186
Zeng W-J, Xiong C-M, Zhao L, et al., 2012, Atorvastatin in Pulmonary Arterial Hypertension (APATH) study, EUROPEAN RESPIRATORY JOURNAL, Vol: 40, Pages: 67-74, ISSN: 0903-1936
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- Citations: 47
Nasim MT, Ogo T, Chowdhury HM, et al., 2012, BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGF-TAK1-MAPK pathways in PAH, HUMAN MOLECULAR GENETICS, Vol: 21, Pages: 2548-2558, ISSN: 0964-6906
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- Citations: 56
Wojciak-Stothard B, Zhao L, Oliver E, et al., 2012, Role of RhoB in the Regulation of Pulmonary Endothelial and Smooth Muscle Cell Responses to Hypoxia, CIRCULATION RESEARCH, Vol: 110, Pages: 1423-+, ISSN: 0009-7330
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- Citations: 67
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