Pulmonary Hypertension Group
The Pulmonary Hypertension Study Group, within the Centre for Pharmacology and Therapeutics, is closely associated with the clinical pulmonary hypertension service at Imperial. An electronic database, TRIPHIC, captures clinical interactions with the NHS Trust and enables patient-orientated research. Studies on patients are used to inform basic research and new ideas tested in silico and in vitro and translated back into patient care. The NIHR Imperial Clinical Research Facility offers an appropriate environment for patient studies.
A major ongoing research programme, funded by the BHF and MRC and involving all the major UK centres specialising in the management of pulmonary hyopertension, is concerned with mapping the genetic architecture of idiopathic and hereditary pulmonary arterial hypertension and exploring molecular subtypes using proteomics, metabolomics and transcriptomics. These studies, involving a cohort of over 300 patients from Hammersmith Hospital, have identified plasma proteins and metabolic signatures that predict survival and may offer novel therapeutic targets for future study.
The evaluation of novel therapeutic agents in patients has become a challenge, as treatments move away from vasorelaxant drugs to agents that address the structural remodelling that characterises the disease. Advances in imaging offer a solution. The use of molecular imaging (e.g. PET-CT) to inform on the pharmacology of a drug in patients and cardiac magnetic resonance as a non-invasive tool for studying clinically meaningful drug response has been pioneered at Imperial.
An important cause of pulmonary hypertension is hypoxia. Careful studies of the mechanisms by which mammals adapt to high-altitude life, where oxygen levels are low, can provide insight into molecular pathways for maintaining pulmonary vascular homeostasis. This approach has recently unmasked the role of a zinc transporter in pulmonary hypertension and ongoing studies in Kyrzyg highlanders and Tibetans are expected to reveal more.
The group is keen to develop in vitro human models of pulmonary vascular disease for high throughput testing of disease mechanisms and drug effects. To this end pulmonary endothelial and smooth muscle cells are being grown a microfluidic environment that can be directly observed using microscopy and sampled for analysis and the result tested for opportunities to inform pulmonary vascular research.
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Funding
Our group is generously supported by the following grant agencies/charities:
Recent publications
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 MR. The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia. Nature. 2015 Aug 10. doi: 10.1038/nature14620
Cotroneo E, Ashek A, Wang L, Wharton J, Dubois O, Bozorgi S, Busbridge M, Alavian KN, Wilkins MR, Zhao L.Iron homeostasis and pulmonary hypertension: iron deficiency leads to pulmonary vascular remodeling in the rat. Circ Res. 2015 May 8;116(10):1680-90
Iannone L, Zhao L, Dubois O, Duluc L, Rhodes CJ, Wharton J, Wilkins MR, Leiper J, Wojciak-Stothard B.miR-21/DDAH1 pathway regulates pulmonary vascular responses to hypoxia. Biochem J. 2014 Aug 15;462(1):103-12
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 JS, Wharton J, Zhao L, Wilkins MR. Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension. Circulation. 2014 Apr 29;129(17):1770-80
Zhao L, Ashek A, Wang L, Fang W, Dabral S, Dubois O, Cupitt J, Pullamsetti SS, Cotroneo E, Jones H, Tomasi G, Nguyen QD, Aboagye EO, El-Bahrawy MA, Barnes G, Howard LS, Gibbs JS, Gsell W, He JG, Wilkins MR. Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments. Circulation. 2013 Sep 10;128(11):1214-24
Zhao L, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, Wang D, Li M, McKinsey TA, Stenmark KR, Wilkins MR. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation. 2012 Jul 24;126(4):455-67.
Wojciak-Stothard B, Zhao L, Oliver E, Dubois O, Wu Y, Kardassis D, Vasilaki E, Huang M, Mitchell JA, Harrington LS, Prendergast GC, Wilkins MR. Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia. Circ Res. 2012 May 25;110(11):1423-3
Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs JS, Wharton J, Wilkins MR. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol. 2011 Jul 12;58(3):300-9.
Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol. 2011 Jun 21;8(8):443-55.
Rhodes CJ, Wharton J, Howard LS, Gibbs JS, Wilkins MR. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart. 2011 Jul;97(13):1054-60.
Rhodes CJ, Wharton J, Howard L, Gibbs JS, Vonk-Noordegraaf A, Wilkins MR. Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target. Eur Respir J. 2011 May 20. [Epub ahead of print] .