Research Summary
Lab members
- Dr MD Ali Ashek
(Research Associate) - Chien-Nien Chen
(Research Associate) - Dr Nicoleta Baxan
(Research Associate) - Mr Olivier D Dubois
(Biomedical Sciences Technician) - Lin Zhao
(PhD student) - Marili Niglas
(PhD Student) - Farah Sabrin
(PhD student) - Iyobel Kibread
(PhD student)
Key publications
(1) Walters R, Vasilaki E, Aman J, Chen CN, Wu YK, Liang OD,Ashek A, Dubois D, Zhao L, Sabrin F, Cebola I, Ferrer J, Morrell NW, Klinger JR, Wilkins MR, Zhao L*, Rhodes CJ*. SOX17 Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension. Circulation 2023;147:1606–1621(Corresponding author)
Common PAH risk variants upstream of the SOX17 promoter reduce endothelial SOX17 expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature.
(2) Yeh FC, Chen CN, Xie CY, Baxan N, Zhao Lin, Ashek A, Sabrin F, Lawrie A, Wilkins WR, Zhao L*. TLR7/8 activation induces autoimmune vasculopathy and causes severe pulmonary arterial hypertension. Eur Respir J 2023; 62: 2300204 (Corresponding author)
This study highlights the complex immune–vascular interactions involved in pulmonary vascular diseases associated with autoimmune/infectious disorders.
(3) 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 524: 356-360 (Corresponding author)
This study demonstrates a key role for the zinc transporter, ZIP12, in vascular remodeling in pulmonary hypertension. It has opened a new field of research into the importance of zinc homeostasis in pulmonary vascular disease.
(4) 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 116: 1680-1690 (Corresponding author)
Here we demonstrate that iron deficiency per se can lead to pulmonary vascular remodeling and provide mechanistic insight into the link between iron deficiency and survival in pulmonary arterial hypertension (Accompanied by editorial Sutendra G, Bonnet S. Circ Res. 2015 May 8;116(10):1636-8).
(5) Zhao L*, Ashek A, Wang L, Fang W, Dabral S, Dubois O, Cupitt J, Pullamsetti SS, Cotroneo E, Jones H, Tomasi G, Nguyen GD, Aboagye EO, El-Bahrawy MA, Barnes G, Howard LS, Gibbs SR, Gsell W, He JG, and Wilkins MR. Heterogeneity in lung 18FDG uptake in PAH: potential of dynamic 18FDG-PET with kinetic analysis as a bridging biomarker for pulmonary remodeling targeted treatments. Circulation 2013; 128:1214-1224. (Corresponding author)
A challenge of modern day therapeutics is the demonstration that treatments directed as reversing vascular remodelling achieve this in pulmonary hypertension patients. This study shows the potential of 18F-FDG PET to report vascular cell proliferation and inflammation in patients, and its potential to assess drug response.
(6) Zhao L*, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, Wan D, Li M, McKinsey TA, Stenmark KR and Wilkins MR. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) Circulation 2012 126:455-467. (Corresponding author)
This study made the interesting observation of epigenetic impact in idiopathic pulmonary hypertension patient and reported the effectiveness of the HDAC inhibitors in the in vitro and in vivo model, supporting a therapeutic strategy based on HDAC inhibition in pulmonary hypertension.
(7) Francis B, Wilkins MR, Zhao L*. Tetrahydrobiopterin (BH4) and the regulation of hypoxic pulmonary vasoconstriction. Eur Resp J 2010 36:323-330. (Corresponding author)
We demonstrated that the bioavailability of nitric oxide synthases cofactor BH4 is an important determinant of the pulmonary vascular response to hypoxia, mediated via nitric oxide, hydrogen peroxide and its antioxidant properties, and are attenuated by oxidant stress. (Accompanied by front cover and editorial Weir E.K. Hong Z and Chen Y. Eur Resp J 2010 36:234-236) .
(8) Zhao L*, Sebkhi A, Ali O, Wojciak-stothard B, Mamanova L, Yang Q, Wharton J, Wilkins MR. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. Eur Resp J 2009 34(4): 948-57. (Corresponding author)
In parallel to a clinical study, we demonstrated that simvastatin can be usefully combined with sildenafil in the treatment of pulmonary arterial hypertension in rodent model to achieve greater therapeutic benefit, due to an additive effect on eNOS expression and cGMP levels in the lung and right ventricle, and a more marked inhibition of RhoA activity.
(9) Khoo JP*, Zhao L*, Alp NJ, Bendall JK, Nicoli T Rockett K, Wilkins MR, Channon KM. A pivotal role of endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation 2005 111:2126-33.
This phenotype-driven study presented the hph-1 mouse with marked pulmonary vascular remodeling as a result of GTP cyclohydrolase-1 defect (from ENU mutagenesis) causing deficiency of endogenous tetrahydrobiopterin (a co-factor for NO synthases) production, and demonstrated that endothelial BH4 availability is essential for maintaining pulmonary vascular homeostasis.
(10) Zhao L, Sebkhi A, Nunes DJ, Long L, Haley CS, Szpirer J, Szpirer C, Williams AJ, Wilkins MR. Right ventricular hypertrophy secondary to pulmonary hypertension is linked to rat chromosome 17: Evaluation of cardiac ryanodine Ryr2 receptor as a candidate. Circulation 2001; 103 442-447.
This study was the first to demonstrate a susceptibility locus for hypoxia-induced pulmonary hypertension in the rat and laid the basis for identifying Slc39a12 as the responsible gene â described in Zhao et al Nature 2015.
(11) Zhao L, Mason NA, Strange JW, Walker H, Wilkins MR. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic peptide activity. Circulation 2003 107:234-237.
Studying the effect of sildenafil in mice lacking functional guanylyl cyclaseâlinked natriuretic peptide receptor NPR-A exposed to hypoxia, we demonstrated that a functional natriuretic peptide pathway is crucial to the effective reduction of hypoxia-induced pulmonary vascular remodelling by sildenafil.
(12) Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001 104:424-428.
This study is the first in a series from our lab investigating PDE5 as a drug target in human pulmonary hypertension. It contributed to the documentation that led to the licensing of sildenafil as a treatment for the disease.