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
to

100 results found

Smadja DM, Philippe A, Ferreira EVM, Oliveira RKF, McCabe C, Zhao Let al., 2024, CD147 Plasma Levels in Hospitalised Patients with Covid-19 Pneumonia Predict Illness Severity and In-Hospital Mortality., Stem Cell Rev Rep, Vol: 20, Pages: 568-572

COVID-19 and infectious diseases have been included in strategic development goals (SDG) of United Nations (UN). The CD147 receptor is one of several receptors for the SARS-CoV-2 spike protein that could mediate Covid-19 viral infection of host cells. It has been recently proposed to regulate viral invasion and dissemination among lymphocytes and progenitor/stem cells. A soluble by-product of CD147 (sCD147) exists in plasma and has been previously identified as a marker of diabetes and platelet activation. We examined plasma sCD147 levels in 161 Covid-19 patients at hospital admission. We demonstrated significantly higher plasma sCD147 levels in Covid-19 patients, which correlated with plasma multiorgan dysfunction biomarkers interleukin-6, creatinine and Troponin I. Importantly, sCD147 admission levels were associated with Covid-19 severity and survival, carrying potential value as a biomarker in hospitalized patients with Covid-19 infection.

Journal article

Knight H, Abis G, Kaur M, Green HLH, Krasemann S, Hartmann K, Lynham S, Clark J, Zhao L, Ruppert C, Weiss A, Schermuly RT, Eaton P, Rudyk Oet al., 2023, Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation., Circ Res, Vol: 133, Pages: 966-988

BACKGROUND: Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH. METHODS: Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH. RESULTS: Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hypera

Journal article

Judina A, Niglas M, Leonov V, Kirkby NS, Diakonov I, Wright PT, Zhao L, Mitchell JA, Gorelik Jet al., 2023, Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function., Cells, Vol: 12

(1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil's synergy with isoprenaline in RV and LV cardiomyocytes. We hypothesised that disease-related RV structural changes in cardiomyocytes would reduce contractile responses and cAMP/PKA signalling activity. (2) We induced PH in male Sprague Dawley rats using monocrotaline and isolated their ventricular cardiomyocytes. The effect of in vitro treprostinil and isoprenaline stimulation on contraction was assessed. FRET microscopy was used to study PKA activity associated with treprostinil stimulation in AKAR3-NES FRET-based biosensor-expressing cells. (3) RV cells exhibited maladaptive remodelling with hypertrophy, impaired contractility, and calcium transients compared to control and LV cardiomyocytes. Combining treprostinil and isoprenaline failed to enhance inotropy in PH RV cardiomyocytes. PH RV cardiomyocytes displayed an aberrant contractile behaviour, which the combination treatment could not rectify. Finally, we observed decreased PKA activity in treprostinil-treated PH RV cardiomyocytes. (4) PH-associated RV cardiomyocyte remodelling reduced treprostinil sensitivity, inotropic support, and impaired relaxation. Overall, this study highlights the complexity of RV dysfunction in advanced PH and suggests the need for alternative therapeutic strategies.

Journal article

Chen C-N, Hajji N, Yeh F-C, Rahman S, Ali S, Wharton J, Baxan N, Zhao L, Xie C-Y, Chen Y-G, Frid MG, Chelladurai P, Pullamsetti SS, Stenmark KR, Wilkins MR, Zhao Let al., 2023, Restoration of Foxp31 regulatory T cells by HDAC-dependent epigenetic modulation plays a pivotal role in resolving pulmonary arterial hypertension pathology, American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 879-895, ISSN: 1073-449X

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from idiopathic PAH (IPAH) patients and rodent models of pulmonary hypertension (PH): monocrotaline (MCT), Sugen5416-hypoxia (SuHx) rats and Treg-depleted mice. HDAC inhibitor Vorinostat (SAHA) was used to examine the immune modulatory effects in vivo, ex vivo and in vitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased programmed cell death-1 (PD-1) signalling in PBMCs from IPAH patients. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in SuHx mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDACi is a promising approach to resolve PH pathology, highlighting the potential benefit of developing "epigenetic therapies” for PAH.

Journal article

Yeh F-C, Chen C-N, Xie C-Y, Baxan N, Zhao L, Ashek A, Sabrin F, Lawrie A, Wilkins M, Zhao Let al., 2023, TLR7/8 activation induces autoimmune vasculopathy and causes severe pulmonary arterial hypertension, European Respiratory Journal, Vol: 62, ISSN: 0903-1936

Journal article

Walters R, Vasilaki E, Aman J, Chen C-N, Wu Y, Liang OD, Ashek A, Dubois O, Zhao L, Sabrin F, Cebola I, Ferrer J, Morrell NW, Klinger JR, Wilkins MR, Zhao L, Rhodes CJet al., 2023, SOX17 enhancer variants disrupt transcription factor binding and enhancer inactivity drives pulmonary hypertension, Circulation, Vol: 147, Pages: 1606-1621, ISSN: 0009-7322

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17, which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development. METHODS: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico-predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17-signal 1 enhancer region (SOX17-4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia. RESULTS: CRISPR inhibition of SOX17-signal 2 and deletion of SOX17-signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of t

Journal article

Samaranayake CB, Kempny A, Naeije R, Gatzoulis M, Price L, Dimopoulos K, Zhao L, Wort SJ, McCabe Cet al., 2023, Beta-blockade improves right ventricular diastolic function in exercising pulmonary arterial hypertension, European Respiratory Journal, Vol: 61, ISSN: 0903-1936

Journal article

Klinger JR, Jeong E, Pereira M, Quesenberry PJ, Zhao L, Wilkins MR, Liang ODet al., 2023, RUNX1 Mediates Pulmonary Hypertension Associated With Impaired SOX17 Expression, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Zhang H, D'Alessandro A, Li M, Reisz JA, Riddle S, Muralidhar A, Bull T, Zhao L, Gerasimovskaya E, Stenmark KRet al., 2023, Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension, Vascular Pharmacology, Vol: 149, Pages: 1-10, ISSN: 1537-1891

RATIONALE: Sildenafil, a well-known vasodilator known to interfere with purinergic signaling through effects on cGMP, is a mainstay in the treatment of pulmonary hypertension (PH). However, little is known regarding its effects on the metabolic reprogramming of vascular cells, which is a hallmark of PH. Purine metabolism, especially intracellular de novo purine biosynthesis is essential for vascular cell proliferation. Since adventitial fibroblasts are critical contributors to proliferative vascular remodeling in PH, in this study we aimed to investigate if sildenafil, beyond its well-known vasodilator role in smooth muscle cells, impacts intracellular purine metabolism and proliferation of fibroblasts derived from human PH patients. METHODS: Integrated omics approaches (plasma and cell metabolomics) and pharmacological inhibitor approaches were employed in plasma samples and cultured pulmonary artery fibroblasts from PH patients. MEASUREMENTS AND MAIN RESULTS: Plasma metabolome analysis of 27 PH patients before and after treatment with sildenafil, demonstrated a partial, but specific effect of sildenafil on purine metabolites, especially adenosine, adenine, and xanthine. However, circulating markers of cell stress, including lactate, succinate, and hypoxanthine were only decreased in a small subset of sildenafil-treated patients. To better understand potential effects of sildenafil on pathological changes in purine metabolism (especially purine synthesis) in PH, we performed studies on pulmonary fibroblasts from PAH patients (PH-Fibs) and corresponding controls (CO-Fibs), since these cells have previously been shown to demonstrate stable and marked PH associated phenotypic and metabolic changes. We found that PH-Fibs exhibited significantly increased purine synthesis. Treatment of PH-Fibs with sildenafil was insufficient to normalize cellular metabolic phenotype and only modestly attenuated the proliferation. However, we observed that treatments which have been sho

Journal article

Judina A, Endo A, Zhao L, Niglas M, Wright P, Kirkby N, Mitchell J, Gorelik Jet al., 2022, Activation of prostacyclin (PGI2) IP receptors by treprostinil in the right atrium is associated with stronger fibroblast PKA response, 24th World Congress of the International-Society-for-Heart-Research, Publisher: ELSEVIER SCI LTD, Pages: S156-S157, ISSN: 0022-2828

Conference paper

Sydykov A, Petrovic A, Maripov AM, Gredic M, Bermes DG, Kushubakova N, Uulu KM, Pilz C, Cholponbaeva M, Duishobaev M, Satybaldyev S, Satieva N, Mamazhakypov A, Sartmyrzaeva M, Omurzakova N, Kerimbekova Z, Baktybek N, Kulchoroeva C, Pak O, Zhao L, Weissmann N, Avdeev S, Maslov LN, Ghofrani HA, Schermuly RT, Sarybaev AS, Kosanovic Det al., 2022, Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season, CELLS, Vol: 11

Journal article

Samaranayake C, Niglas M, Kempny A, Baxan N, Ashek A, Pinguel J, Dimopoulos K, Price LC, Wort SJ, Zhao L, Mccabe Cet al., 2022, Acute beat blockade improves right ventricular diastolic filling in pulmonary arterial hypertension: a rodent CMR and clinical human pressure-volume study, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Samaranayake C, Kempny A, Price LC, Pinguel J, Morris E, Moriarty E, Gummadi M, Dimopoulos K, Wort SJ, Zhao L, Mccabe Cet al., 2022, Metabolic modulation of the right ventricle and pulmonary circulation in pulmonary arterial hypertension: an interventional study using a Glucagon-like-peptide-1 (GLP-1) agonist, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Liu J, Yang P, Tian H, Zhen K, McCabe C, Zhao L, Zhai Zet al., 2022, Right ventricle remodeling in chronic thromboembolic pulmonary hypertension, JOURNAL OF TRANSLATIONAL INTERNAL MEDICINE, Vol: 10, Pages: 125-133, ISSN: 2450-131X

Journal article

Liang O, Jeong E, Pereira M, So E, Del Tatto M, Wen S, Dooner M, Ventetuolo CE, Quesenberry PJ, Zhao L, Wilkins MR, Klinger JRet al., 2022, RUNX1 Is Required for the Development of Pulmonary Arterial Hypertension, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

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 MA, Rhodes CJ, Richter MJ, Gall H, Ghofrani HA, Zhao L, Huson L, Wilkins MRet al., 2022, Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials (vol 18, pg 981, 2021), ANNALS OF THE AMERICAN THORACIC SOCIETY, Vol: 19, Pages: 703-703, ISSN: 1546-3222

Journal article

Botros L, Jansen SMA, Ashek A, Spruijt OA, Tramper J, Noordegraaf A, 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, Pulmonary Circulation, Vol: 11, ISSN: 2045-8940

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-PE

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., Annals of the American Thoracic Society, Vol: 18, Pages: 981-988, ISSN: 1546-3222

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

Chen CN, Zhao L, Rhodes C, Zhao Let al., 2021, Pathobiology of Pulmonary Hypertension, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 530-541, ISBN: 9780081027233

Pulmonary hypertension (PH) is a disease of progressive pulmonary vascular remodeling. The complexity of PH pathology, characterized by inflammation and dysregulated growth of pulmonary vascular cells, challenges current treatments. Clinical and translational research has played a major role in advancing our understanding of pathobiological mechanisms intrinsic to PH pathology, providing insights into new therapeutic targets.

Book chapter

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

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

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

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

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