Imperial College London

ProfessorLanZhao

Faculty of MedicineNational Heart & Lung Institute

Professor of Experimental Medicine
 
 
 
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Contact

 

+44 (0)20 7594 6823l.zhao

 
 
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Location

 

531ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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81 results found

Botros L, Jansen SMA, Ashek A, Spruijt OA, Tramper J, Noordegraaf AV, Aman J, Harms H, de Man FS, Huisman MC, Zhao L, Bogaard HJet al., 2021, Application of [18F]FLT-PET in pulmonary arterial hypertension: a clinical study in pulmonary arterial hypertension patients and unaffected bone morphogenetic protein receptor type 2 mutation carriers., Pulm Circ, Vol: 11, ISSN: 2045-8932

Pulmonary arterial hypertension is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3'-deoxy-3'-[18F]-fluorothymidine (18FLT) positron emission tomography (PET) scanning was increased in pulmonary arterial hypertension patients, hence providing a possible biomarker for pulmonary arterial hypertension as it reflects vascular cell hyperproliferation in the lung. This study sought to validate 18FLT-PET in an expanded cohort of pulmonary arterial hypertension patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 mutation carriers. 18FLT-PET scanning was performed in 21 pulmonary arterial hypertension patients (15 hereditary pulmonary arterial hypertension and 6 idiopathic pulmonary arterial hypertension), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung 18FLT k3 phosphorylation among pulmonary arterial hypertension patients, unaffected bone morphogenetic protein receptor type 2 mutation carriers and healthy controls. Lung 18FLT uptake did not correlate with haemodynamic or clinical parameters in pulmonary arterial hypertension patients. Sequential 18FLT-PET scanning in three patients demonstrated uneven regional distribution in 18FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. We did not detect significantly increased lung 18FLT uptake in pulmonary arterial hypertension patients, nor in the unaffected bone morphogenetic protein receptor type 2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human 18FLT report may be explained by a small sample size previously and we observed large variation of lung 18FLT signals between patients, challenging the application of 18FLT-PET as a bioma

Journal article

Howard LSGE, He J, Watson GMJ, Huang L, Wharton J, Luo Q, Kiely DG, Condliffe R, Pepke-Zaba J, Morrell NW, Sheares KK, Ulrich A, Quan R, Zhao Z, Jing X, An C, Liu Z, Xiong C, Robbins PA, Dawes T, de Marvao A, Rhodes CJ, Richter MJ, Gall H, Ghofrani HA, Zhao L, Huson L, Wilkins MRet al., 2021, Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials., Ann Am Thorac Soc

RATIONALE: Iron deficiency, in the absence of anaemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin levels. The safety and benefit of parenteral iron replacement in this patient population is unclear. OBJECTIVES: To evaluate the safety and efficacy of parenteral iron replacement in pulmonary arterial hypertension. METHODS: In two randomised, double blind, placebo-controlled 12 week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject®) 1000 mg (or 15 mg/kg if weight < 66.7Kg) or saline as placebo and 17 patients in China received iron dextran (Cosmofer®) 20 mg iron/kg body weight or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by: a serum ferritin < 37 µg/l or iron < 10.3 µmol/l or transferrin saturations < 16.4%. RESULTS: Both iron treatments were well tolerated and improved iron status. Analysed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6 minute walk test) or cardio-pulmonary haemodynamics, as assessed by right heart catheterisation, cardiac magnetic resonance or plasma NT-proBNP, at 12 weeks. CONCLUSION: Iron repletion by administration of a slow release iron preparation as a single infusion to PAH patients with iron deficiency without overt anaemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).

Journal article

Wu Y, Wharton J, Walters R, Vasilaki E, Aman J, Zhao L, Wilkins MR, Rhodes CJet al., 2021, The pathophysiological role of novel pulmonary arterial hypertension gene SOX17., European Respiratory Journal, Vol: 57, ISSN: 0903-1936

Pulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural re-modelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole genome and exome sequencing studies have identified SOX17 as a novel risk gene in PAH, with a dominant mode of inheritance and incomplete penetrance. Rare deleterious variants in the gene and more common variants in upstream enhancer sites have both been associated with the disease and a deficiency of SOX17 expression may predispose to PAH. This review aims to consolidate the evidence linking genetic variants in SOX17 to PAH and explores the numerous targets and effects of the transcription factor, focussing on the pulmonary vasculature and the pathobiology of PAH.

Journal article

Gassmann M, Cowburn A, Gu H, Li J, Rodriguez M, Babicheva A, Jain PP, Xiong M, Gassmann NN, Yuan JX-J, Wilkins MR, Zhao Let al., 2021, Hypoxia-induced pulmonary hypertension - utilising experiments of nature, British Journal of Pharmacology, Vol: 178, Pages: 121-131, ISSN: 0007-1188

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest to understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature; specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather that cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation.

Journal article

Chelladurai P, Dabral S, Basineni SR, Chen C-N, Schmoranzer M, Bender N, Feld C, Noetzold RR, Dobreva G, Wilhelm J, Jungblut B, Zhao L, Bauer U-M, Seeger W, Pullamsetti SSet al., 2020, Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension, Scientific Reports, Vol: 10, Pages: 1-20, ISSN: 2045-2322

Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circu

Journal article

Clough TJ, Baxan N, Coakley EJ, Rivas C, Zhao L, Leclerc I, Martinez-Sanchez A, Rutter GA, Long NJet al., 2020, Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of beta-cell-dependent contrast enhancement in the pancreas, Dalton Transactions: an international journal of inorganic chemistry, Vol: 49, Pages: 4732-4740, ISSN: 1477-9226

Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.

Journal article

Wang L, Xiong C, Li M, Zeng X, Wang Q, Fang W, Zhao Let al., 2020, Assessment of lung glucose uptake in patients with systemic lupus erythematosus pulmonary arterial hypertension: a quantitative FDG-PET imaging study, Publisher: SPRINGER, Pages: 407-414, ISSN: 0914-7187

Conference paper

Howard L, He J-G, Wharton J, Watson G, Gall H, Ghofrani H, Huang L, Kiely D, Luo Q, Sheares K, Zhao L, Wilkins Met al., 2019, Late Breaking Abstract - Supplementation of iron in pulmonary hypertension (SIPHON): results from a randomised controlled crossover trial, European-Respiratory-Society (ERS) International Congress, Publisher: European Respiratory Society, Pages: 1-2, ISSN: 0903-1936

Background: Iron deficiency in the absence of anaemia is common in patients with idiopathic pulmonary arterial hypertension (IPAH). It has been associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis and correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown.Methods: Iron-deficient patients (defined as ferritin <37µg/L, serum iron <10.3µmol/L, transferrin saturation <16.4% or soluble transferrin receptor >28.1nmol/L) were randomised to receive a single infusion of ferric carboxymaltose (FCM) 15 mg/kg up to 1000mg or saline placebo with cross-over after 12 weeks of treatment. The primary outcome was change in endurance time on cardio-pulmonary exercise testing (CPET) at 12 weeks. Secondary measures included resting haemodynamics, incremental CPET, iron indices, 6 minute walk distance, WHO functional class, quality of life score, NT-proBNP and cardiac anatomy and function from MRI.Results: 40 patients enrolled and 39 provided data for analysis. FCM improved iron indices, with a significant increase in ferritin (P=0.0003) and reduction in soluble transferrin receptor levels (P<0.0001) at 12 weeks, and was well tolerated. There was no significant change in endurance time or in any other secondary endpoint. Data from a meta-analysis including a parallel study from Fuwai Hospital, China, will be available at the time of presentation.Conclusion: Iron repletion through a single infusion of FCM improves iron indices and is well tolerated but does not improve exercise capacity in PAH.

Conference paper

Kiely D, Levin D, Hassoun P, Ivy DD, Jone P-N, Bwika J, Kawut SM, Lordan J, Lungu A, Mazurek J, Moledina S, Olschewski H, Peacock A, Puri GD, Rahaghi F, Schafer M, Schiebler M, Screaton N, Tawhai M, Van Beek EJ, Vonk-Noordegraaf A, Vanderpool RR, Wort J, Zhao L, Wild J, Vogel-Claussen J, Swift Aet al., 2019, Statement on imaging and pulmonary hypertension from the Pulmonary Vascular Research Institute (PVRI), Pulmonary Circulation, Vol: 9, Pages: 1-32, ISSN: 2045-8940

Pulmonary hypertension is highly heterogeneous and despite treatment advances it remains a life shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility practice remains variable, dependent in part on imaging availability and expertise. This statement summarises current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected pulmonary hypertension. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling-based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists and computational modelers. Section editors generated a series of summary statements 1based on a review of the literature and professional experience and following consensus review, a diagnostic algorithm and fifty five statements were agreed. The diagnostic algorithm and summary statements, emphasise the key role and added value of imaging in the diagnosis and assessment of pulmonary hypertension and highlight areas requiring further research.

Journal article

Sydykov A, Maripov A, Uulu KM, Kushubakova N, Petrovic A, Vroom C, Cholponbaeva M, Duishobaev M, Satybaldyev S, Satieva N, Mamazhakypov A, Sartmyrzaeva M, Omurzakova N, Kerimbekova Z, Baktybek N, Pak O, Zhao L, Weissmann N, Sarybaev A, Avdeev S, Ghofrani HA, Schermuly RT, Kosanovic Det al., 2019, Pulmonary Vascular Pressure Response to Acute Cold Exposure in Kyrgyz Highlanders, HIGH ALTITUDE MEDICINE & BIOLOGY, Vol: 20, Pages: 375-382, ISSN: 1527-0297

Journal article

Sattler S, Baxan N, Chowdhury R, Rosenthal N, Prasad S, Zhao L, Harding Set al., 2019, Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multi-parametric quantitative cardiac MRI, Disease Models & Mechanisms, Vol: 12, Pages: 1-10, ISSN: 1754-8403

Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the TLR-7 agonist Resiquimod induces auto-antibodies and systemic tissue damage including in the heart, and is used as an inducible mouse model of Systemic Lupus Erythematosus (SLE).Here, we show that over-activation of the TLR-7 pathway of viral recognition by Resiquimod-treatment of CFN mice induces severe thrombocytopenia and internal bleeding which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results to ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed a detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes.In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis will improve interpretation of disease mechanisms and diagnostic sensitivity.

Journal article

Rudyk O, Rowan A, Prysyazhna O, Krasemann S, Hartmann K, Zhang M, Shah AM, Ruppert C, Weiss A, Schermuly RT, Ida T, Akaike T, Zhao L, Eaton Pet al., 2019, Oxidation of PKGI alpha mediates an endogenous adaptation to pulmonary hypertension, Proceedings of the National Academy of Sciences of the United States of America, Vol: 116, Pages: 13016-13025, ISSN: 0027-8424

Chronic hypoxia causes pulmonary hypertension (PH), vascular remodeling, right ventricular (RV) hypertrophy, and cardiac failure. Protein kinase G Iα (PKGIα) is susceptible to oxidation, forming an interprotein disulfide homodimer associated with kinase targeting involved in vasodilation. Here we report increased disulfide PKGIα in pulmonary arteries from mice with hypoxic PH or lungs from patients with pulmonary arterial hypertension. This oxidation is likely caused by oxidants derived from NADPH oxidase-4, superoxide dismutase 3, and cystathionine γ-lyase, enzymes that were concomitantly increased in these samples. Indeed, products that may arise from these enzymes, including hydrogen peroxide, glutathione disulfide, and protein-bound persulfides, were increased in the plasma of hypoxic mice. Furthermore, low-molecular-weight hydropersulfides, which can serve as “superreductants” were attenuated in hypoxic tissues, consistent with systemic oxidative stress and the oxidation of PKGIα observed. Inhibiting cystathionine γ-lyase resulted in decreased hypoxia-induced disulfide PKGIα and more severe PH phenotype in wild-type mice, but not in Cys42Ser PKGIα knock-in (KI) mice that are resistant to oxidation. In addition, KI mice also developed potentiated PH during hypoxia alone. Thus, oxidation of PKGIα is an adaptive mechanism that limits PH, a concept further supported by polysulfide treatment abrogating hypoxia-induced RV hypertrophy in wild-type, but not in the KI, mice. Unbiased transcriptomic analysis of hypoxic lungs before structural remodeling identified up-regulation of endothelial-to-mesenchymal transition pathways in the KI compared with wild-type mice. Thus, disulfide PKGIα is an intrinsic adaptive mechanism that attenuates PH progression not only by promoting vasodilation but also by limiting maladaptive growth and fibrosis signaling.

Journal article

Abdul-Salam V, Russomanno G, Chien-Nien C, Mahomed A, Yates L, Wilkins M, Zhao L, Gierula M, Dubois O, Schaeper U, Endruschat J, Wojciak-Stothard Bet 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.

Journal article

Ashek A, Spruijt OA, Harms HJ, Lammertsma AA, Cupitt J, Dubois O, Wharton J, Dabral S, Pullamsetti SS, Huisman MC, Frings V, Boellaard R, de Man FS, Botros L, Jansen S, Noordegraaf AV, Wilkins MR, Bogaard HJ, Zhao Let 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

Journal article

Michelakis ED, Gurtu V, Webster L, Barnes G, Watson G, Howard L, Cupitt J, Paterson I, Thompson RB, Chow K, O'Regan DP, Zhao L, Wharton J, Kiely DG, Kinnaird A, Boukouris AE, White C, Nagendran J, Freed DH, Wort SJ, Gibbs JSR, Wilkins MRet 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.

Journal article

Rudyk O, Krasemann S, Hartmann K, Prysyazhna O, Zhang M, Weiss A, Zhao L, Schermuly R, Eaton Pet 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

Conference paper

Duluc L, Ahmetaj-Shala B, Mitchell J, Abdul Salam VB, Mahomed AS, Aldabbous L, Oliver E, Iannone L, Dubois OD, Storck EM, Tate EW, Zhao L, Wilkins MR, Wojciak-Stothard Bet 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.

Journal article

Ashek A, Dubois O, Wilkins M, Zhao Let 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

Conference paper

Zhao L, Oliver E, Maratou K, Atanur SS, Dubois OD, Cotroneo E, Chen CN, Wang L, Arce C, Chabosseau PL, Ponsa-Cobas J, Frid MG, Moyon B, Webster Z, Aldashev A, Ferrer J, Rutter GA, Stenmark KR, Aitman TJ, Wilkins MRet 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.

Journal article

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

Journal article

Wilkins MR, Ghofrani H-A, Weissmann N, Aldashev A, Zhao Let al., 2015, Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease, CIRCULATION, Vol: 131, Pages: 582-590, ISSN: 0009-7322

Journal article

Ashek A, Tang SP, Dubois O, Coello C, Ashworth S, Passchier J, Wilkins MR, Zhao Let 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

Conference paper

Francis BN, Hale A, Channon KM, Wilkins MR, Zhao Let al., 2014, Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat, PULMONARY CIRCULATION, Vol: 4, Pages: 462-470, ISSN: 2045-8932

Journal article

Iannone L, Zhao L, Dubois O, Duluc L, Rhodes CJ, Wharton J, Wilkins MR, Leiper J, Wojciak-Stothard Bet al., 2014, miR-21/DDAH1 pathway regulates pulmonary vascular responses to hypoxia, BIOCHEMICAL JOURNAL, Vol: 462, Pages: 103-112, ISSN: 0264-6021

Journal article

Wojciak-Stothard B, Abdul-Salam VB, Lao KH, Tsang H, Irwin DC, Lisk C, Loomis Z, Stenmark KR, Edwards JC, Yuspa SH, Howard LS, Edwards RJ, Rhodes CJ, Gibbs JSR, Wharton J, Zhao L, Wilkins MRet 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.

Journal article

George PM, Oliver E, Dorfmuller P, Dubois OD, Reed DM, Kirkby NS, Mohamed NA, Perros F, Antigny F, Fadel E, Schreiber BE, Holmes AM, Southwood M, Hagan G, Wort SJ, Bartlett N, Morrell NW, Coghlan JG, Humbert M, Zhao L, Mitchell JAet 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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Iannone L, Leiper J, Zhao L, Wilkins MR, Wojciak-Stothard Bet 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

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Cotroneo E, Ashek A, Wharton J, Dubois O, Bozorgi S, Busbridge M, Wilkins M, Zhao Let al., 2014, Pulmonary Vascular Remodelling In The Chronic Iron-Deficient Rat, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X

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Watson G, Oliver E, Zhao L, Wilkins MRet 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.

Journal article

Wang L, Guo L-J, Liu J, Wang W, Yuan JX-J, Zhao L, Wang J, Wang Cet 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

Journal article

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