Imperial College London

Professor Martin Wilkins

Faculty of MedicineDepartment of Medicine

Head of the Department of Medicine
 
 
 
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Contact

 

+44 (0)20 3313 2049m.wilkins

 
 
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Location

 

NIHR / Wellcome Trust Clinical Research FacilityICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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179 results found

Gräf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, Hodgson J, Liu B, Salmon RM, Southwood M, Machado RD, Martin JM, Treacy CM, Yates K, Daugherty LC, Shamardina O, Whitehorn D, Holden S, Aldred M, Bogaard HJ, Church C, Coghlan G, Condliffe R, Corris PA, Danesino C, Eyries M, Gall H, Ghio S, Ghofrani H-A, Gibbs JSR, Girerd B, Houweling AC, Howard L, Humbert M, Kiely DG, Kovacs G, MacKenzie Ross RV, Moledina S, Montani D, Newnham M, Olschewski A, Olschewski H, Peacock AJ, Pepke-Zaba J, Prokopenko I, Rhodes CJ, Scelsi L, Seeger W, Soubrier F, Stein DF, Suntharalingam J, Swietlik EM, Toshner MR, van Heel DA, Vonk Noordegraaf A, Waisfisz Q, Wharton J, Wort SJ, Ouwehand WH, Soranzo N, Lawrie A, Upton PD, Wilkins MR, Trembath RC, Morrell NWet al., 2018, Identification of rare sequence variation underlying heritable pulmonary arterial hypertension., Nat Commun, Vol: 9

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

JOURNAL ARTICLE

Huertas A, Guignabert C, Barberà JA, Bärtsch P, Bhattacharya J, Bhattacharya S, Bonsignore MR, Dewachter L, Dinh-Xuan AT, Dorfmüller P, Gladwin MT, Humbert M, Kotsimbos T, Vassilakopoulos T, Sanchez O, Savale L, Testa U, Wilkins MRet al., 2018, Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases: Highlights from basic research to therapy., Eur Respir J, Vol: 51

The European Respiratory Society (ERS) Research Seminar entitled "Pulmonary vascular endothelium: orchestra conductor in respiratory diseases - highlights from basic research to therapy" brought together international experts in dysfunctional pulmonary endothelium, from basic science to translational medicine, to discuss several important aspects in acute and chronic lung diseases. This review will briefly sum up the different topics of discussion from this meeting which was held in Paris, France on October 27-28, 2016. It is important to consider that this paper does not address all aspects of endothelial dysfunction but focuses on specific themes such as: 1) the complex role of the pulmonary endothelium in orchestrating the host response in both health and disease (acute lung injury, chronic obstructive pulmonary disease, high-altitude pulmonary oedema and pulmonary hypertension); and 2) the potential value of dysfunctional pulmonary endothelium as a target for innovative therapies.

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Dawes TJW, de Marvao A, Shi W, Fletcher T, Watson GMJ, Wharton J, Rhodes CJ, Howard LSGE, Gibbs JSR, Rueckert D, Cook SA, Wilkins MR, O'Regan DPet al., 2017, Machine Learning of Three-dimensional Right Ventricular Motion Enables Outcome Prediction in Pulmonary Hypertension: A Cardiac MR Imaging Study, RADIOLOGY, Vol: 283, Pages: 381-390, ISSN: 0033-8419

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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: 0008-6363

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Ghataorhe P, Rhodes CJ, Harbaum L, Attard M, Wharton J, Wilkins MRet al., 2017, Pulmonary arterial hypertension - progress in understanding the disease and prioritizing strategies for drug development, JOURNAL OF INTERNAL MEDICINE, Vol: 282, Pages: 129-141, ISSN: 0954-6820

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Ghofrani H-A, Humbert M, Langleben D, Schermuly R, Stasch J-P, Wilkins MR, Klinger JRet al., 2017, Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension, CHEST, Vol: 151, Pages: 468-480, ISSN: 0012-3692

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Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmuller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs S, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado R, Ross RM, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner M, Trembath R, Noordegraaf AV, Wilkins MR, Wort SJ, Wharton J, Graf S, Morrell NWet al., 2017, Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension, CIRCULATION, Vol: 136, Pages: 2022-+, ISSN: 0009-7322

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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, 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.

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Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JSR, Lawrie A, Graf S, Morrell NW, Wilkins MRet al., 2017, Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension, CIRCULATION, Vol: 135, Pages: 460-+, ISSN: 0009-7322

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Rhodes CJ, Wharton J, Ghataorhe P, Watson G, Girerd B, Howard LS, Gibbs JSR, Condliffe R, Elliot CA, Kiely DG, Simonneau G, Montani D, Sitbon O, Gall H, Schermuly RT, Ghofrani HA, Lawrie A, Humbert M, Wilkins MRet al., 2017, Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study, LANCET RESPIRATORY MEDICINE, Vol: 5, Pages: 717-726, ISSN: 2213-2600

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Wilkins MR, 2017, Apoptosis signal-regulating kinase 1 inhibition in pulmonary hypertension: too much to ASK?, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 286-288, ISSN: 1073-449X

JOURNAL ARTICLE

Aldabbous L, Abdul-Salam V, McKinnon T, Duluc L, Pepke-Zaba J, Southwood M, Ainscough AJ, Hadinnapola C, Wilkins MR, Toshner M, Wojciak-Stothard Bet al., 2016, Neutrophil Extracellular Traps Promote Angiogenesis: Evidence From Vascular Pathology in Pulmonary Hypertension, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 36, Pages: 2078-2087, ISSN: 1079-5642

JOURNAL ARTICLE

Lythgoe MP, Rhodes CJ, Ghataorhe P, Attard M, Wharton J, Wilkins MRet al., 2016, Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future, PHARMACOLOGY & THERAPEUTICS, Vol: 164, Pages: 195-203, ISSN: 0163-7258

JOURNAL ARTICLE

Wilkins MR, Morrell NW, 2016, Prof. Almaz A. Aldashev (1953-2016) IN MEMORIAM, EUROPEAN RESPIRATORY JOURNAL, Vol: 48, Pages: 990-991, ISSN: 0903-1936

JOURNAL ARTICLE

Cotroneo E, Ashek A, Wang L, Wharton J, Dubois O, Bozorgi S, Busbridge M, Alavian KN, Wilkins MR, Zhao Let al., 2015, Iron Homeostasis and Pulmonary Hypertension Iron Deficiency Leads to Pulmonary Vascular Remodeling in the Rat, CIRCULATION RESEARCH, Vol: 116, Pages: 1680-1690, ISSN: 0009-7330

JOURNAL ARTICLE

D'Armini AM, Ghofrani H-A, Kim NH, Mayer E, Morsolini M, Pulido-Zamudio T, Simonneau G, Wilkins MR, Curram J, Davie N, Hoeper MMet al., 2015, Use of responder threshold criteria to evaluate the response to treatment in the phase III CHEST-1 study, JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 34, Pages: 348-355, ISSN: 1053-2498

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Ruiter G, Manders E, Happe CM, Schalij I, Groepenhoff H, Howard LS, Wilkins MR, Bogaard HJ, Westerhof N, van der Laarse WJ, de Man FS, Vonk-Noordegraaf Aet al., 2015, Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency, PULMONARY CIRCULATION, Vol: 5, Pages: 466-472, ISSN: 2045-8932

JOURNAL ARTICLE

Simonneau G, D'Armini AM, Ghofrani H-A, Grimminger F, Hoeper MM, Jansa P, Kim NH, Wang C, Wilkins MR, Fritsch A, Davie N, Colorado P, Mayer Eet al., 2015, Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2), EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 1293-1302, ISSN: 0903-1936

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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

Zhao L, Oliver E, Maratou K, Atanur SS, Dubois OD, Cotroneo E, Chen C-N, 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-U229, ISSN: 0028-0836

JOURNAL ARTICLE

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

JOURNAL ARTICLE

Hoeper M, Kim NH, Mayer E, Pulido T, Wilkins MR, Simonneau G, Torbicki A, Wang C, Davie N, Fritsch A, Ghofrani H-Aet al., 2014, Effects Of Riociguat In Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension (cteph) Vs Persistent/recurrent Pulmonary Hypertension (ph) After Pulmonary Endarterectomy (pea): 1-Year Results From The Chest-2 Study, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X

JOURNAL ARTICLE

Wilkins MR, 2014, Pulmonary hypertension: the value of experimental medicine in new drug development, PULMONARY CIRCULATION, Vol: 4, Pages: 149-150, ISSN: 2045-8932

JOURNAL ARTICLE

Wilkins MR, Aldashev AA, Wharton J, Rhodes CJ, Vandrovcova J, Kasperaviciute D, Bhosle SG, Mueller M, Geschka S, Rison S, Kojonazarov B, Morrell NW, Neidhardt I, Surmeli NB, Aitman TJ, Stasch J-P, Behrends S, Marletta MAet al., 2014, alpha 1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 7, Pages: 920-U505, ISSN: 1942-325X

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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

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Ghofrani H-A, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang Cet al., 2013, Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 369, Pages: 319-329, ISSN: 0028-4793

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Grieve AP, Chow S-C, Curram J, Dawe S, Harnisch LO, Henig NR, Hung HMJ, Ivy DD, Kawut SM, Rahbar MH, Xiao S, Wilkins MRet al., 2013, Advancing clinical trial design in pulmonary hypertension, PULMONARY CIRCULATION, Vol: 3, Pages: 217-225, ISSN: 2045-8932

JOURNAL ARTICLE

Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DBet al., 2013, Definitions and Diagnosis of Pulmonary Hypertension, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 62, Pages: D42-D50, ISSN: 0735-1097

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Howard LSGE, Watson GMJ, Wharton J, Rhodes CJ, Chan K, Khengar R, Robbins PA, Kiely DG, Condliffe R, Elliott CA, Pepke-Zaba J, Sheares K, Morrell NW, Davies R, Ashby D, Gibbs JSR, Wilkins MRet al., 2013, Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension, PULMONARY CIRCULATION, Vol: 3, Pages: 100-107, ISSN: 2045-8932

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Rhodes CJ, Wharton J, Boon RA, Roexe T, Tsang H, Wojciak-Stothard B, Chakrabarti A, Howard LS, Gibbs JSR, Lawrie A, Condliffes R, Elliot CA, Kielys DG, Huson L, Ghofrani HA, Tiede H, Schermuly R, Zeihers AM, Dimmeler S, Wilkins MRet al., 2013, Reduced MicroRNA-150 Is Associated with Poor Survival in Pulmonary Arterial Hypertension, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, Pages: 294-302, ISSN: 1073-449X

JOURNAL ARTICLE

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