Professor of Public Engagement with History
I. NADPH oxidase and reactive oxygen species (ROS) regulation of endothelial function
Endothelial dysfunction characterised by excess production of reactive oxygen species (ROS) is a key early event in the development of many cardiovascular diseases. We are one of the world leading groups in the research area of endothelial oxidative stress and NADPH oxidase. We have demonstrated, at both molecular and functional levels that Nox2 enzyme is expressed constitutionally in endothelial cells and represents a major source of ROS production under pathological conditions. We have shown that the activity of Nox2 enzyme can be upregulated by Angiotensin II, TNFα and high glucose. Increased ROS production by Nox2 enzyme outstrips NO and causes endothelial dysfunction. In particular, we have discovered that the serine phosphorylation of p47phox (a major regulatory subunit of Nox2 enzyme) is a prerequisite of endothelial Nox2 enzyme activation. Knockout of p47phox or inhibition of Nox2 activation reduces the levels of angiotensin II-induced endothelial oxidative stress, high blood pressure and cardiac hypertrophy.
II. Redox-signalling regulation of cardiovascular cell growth, apoptosis and remodelling
Cardiovascular cells (including cardiac myocytes, smooth muscle cells, endothelial cells, pericytes and fibroblasts) express constitutively a multi-subunit NADPH oxidase. Under physiological condition, the activity of this enzyme is low and the small amount of ROS thus generated has been suggested to modulate redox-sensitive signalling pathways required for normal cell function. However, the activity of this enzyme can be up-regulated under pathophysiological conditions. Enhanced oxidant signalling is involved in the development of atherosclerosis, hypertension, cardiac hypertrophy and heart failure. Our recent studies have shown that members of mitogen-activated kinases (MAPKs) family and several cell apoptosis related gene products are redox-sensitive and serve as down-stream signalling pathways for NADPH oxidase. We are in the process to identify novel key signalling molecules that are involved in redox-regulation of cardiac cell hypertrophy, apoptosis and remodelling.
III. Oxidative stress in the pathogenesis of insulin resistance and type 2 diabetes
Endothelial dysfunction attributable to increased ROS generation from NADPH oxidase has emerged as an important pathogenic co-factor linking insulin resistance with the development of long-term cardiovascular complications. Clinical studies have also reported that in diabetic patients undergoing coronary artery bypass surgery, NADPH oxidase subunit expression and activity in their vessels were significantly higher than that from non-diabetics. Using animal models of high-fat diet-induced obesity and insulin resistance we have discovered an increased ROS production due to NADPH oxidase activation in multiple organs of obese animals. Oxidative stress is accompanied with eNOS uncoupling and reduce NO production in aortic vessels and premature endothelial stem cell ageing. We aim to identify the mechanisms through which high glucose and insulin lead to endothelial cell dysfunction and apoptosis.
IV. Aging, vascular dementia and redox-regulation of vascular stem cell biology
Aging is a primary risk factor for the development of many cardiovascular diseases and vascular dementia. Our recent data have shown that Nox2 activation in response to aging-associated hyperglycaemia and hyperinsulinaemia plays a key role in the oxidative damage of vascular function. Inhibition or knockout of Nox2 preserves endothelial function and improves global metabolism in old age. We have found a crucial role of Nox2 -derived oxidative stress in ageing-associated cerebral microvascular damage and endothelial death. We are interested in using pluripotent cells derived from bone marrow hematopoietic stem cells to repair damaged vessels. We are applying the latest stem cell technology to investigate how Nox2-derived ROS affects these cell function and its relationship with the development of vascular dementia.
V. Drug development and invention of novel Nox2 inhibitors
Compelling evidence have highlighted a close relationship between the levels of Nox2 activation and the degree of cardiovascular damage in patients with metabolic and cardiovascular diseases and neurodegenerative diseases. Targeting Nox2 can present a rational and effective approach to reduce oxidative stress in these diseased conditions. Based on the mechanistic information of Nox2 activation discovered by our own researches, we have developed compounds (LMH001-36) that inhibit specifically Nox2 activation with the potential as drug candidates to treat oxidative stress-related cardiovascular diseases and neurodegenerative diseases. We are in the process to characterise the PKPD of our novel Nox2 inhibitors in comparison to other available Nox2 inhibitors. We are working closely with scientists, clinicians and pharmaceutical companies to develop novel drugs and therapies for the treatment of oxidative stress-related human diseases.
1. L.M. Fan, S. Cahill-Smith, L. Geng, J. Du, G. Brooks, J-M. Li. Aging-associated metabolic disorder induces Nox2 activation and oxidative damage of endothelial function. Free Rad. Biol. Med. 2017; 108: 940-951.
2. Whiteley, M.S., S.J. Dos Santos, C.T.D. Lee, and J-M. Li. Mechanochemical ablation causes endothelial and medial damage to the vein wall resulting in deeper penetration of sclerosant compared to sclerotherapy alone in extra-fascial great saphenous vein using an ex vivo model. J.Vasc.Surg. Venous and Lymphatic Disorders. 2017;5:370-377.
3. Meijles D.N., L.M. Fan, M.M. Ghazaly, B. Howlin, M. Krönke, G. Brooks, and J-M. Li. p22phox C242T SNP inhibits inflammatory oxidative damage to endothelial cells and vessels. Circulation. 2016;133:2391-2403.
4. Whiteley, M.S., S.J. Dos Santos, J. T.J. Fernandez-Hart, C.T. D. Lee, and J-M. Li. Media damage following detergent sclerotherapy appears to be secondary to the induction of inflammation and apoptosis: an immunohistochemical study elucidating previous histological observations. Eur J Vasc Endovasc Surg. 2016;51:421-428.
5. Fan, L.M., G. Douglas, J.K. Bendall, E. McNeill, M. J. Crabtree, A. B. Hale, A. Mai, J-M. Li, M. A. McAteer, J. E. Schneider, R. P. Choudhury, and K. M. Channon. Endothelial Cell-Specific ROS Production Increases Susceptibility to Aortic Dissection. Circulation. 2014;129:2661-2672.
6. Meijles D.N., L.M. Fan, B. J. Howlin, and J-M. Li. Molecular Insights of p47phox Phosphorylation Dynamics in the Regulation of NADPH Oxidase Activation and Superoxide Production. J. Biol. Chem. 2014; 289:22759-22770.
7. Fan L.M. and J-M. Li. Evaluation of methods of detecting cell reactive oxygen species production for drug screening and cell cycle studies. Br. J. Pharmacol. Toxicol. Methods. 2014; 70:40-47.
8. Cahill-Smith S and Li J-M. Oxidative stress, redox-signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: A role of NADPH oxidase 2. British J. Clin. Pharmacology. 2014;78:441-453.
9. Du, J., L. M. Fan, A. Mai, and J-M. Li. Crucial roles of Nox2-derived oxidative stress in deteriorating insulin receptor and endothelial function in dietary obesity of mice after middle age. Br. J. Pharmacol. 2013;170:1064-1077.
10. Meijles, D., B. Howlin, and J-M. Li. Consensus in silico computational modelling of the p22phox subunit of the NADPH oxidase. Computational Biol. and Chem. 2012; 39:6-13.
11. Teng, L., L. M. Fan, D. Meijles, and J-M. Li. Divergent effects of p47phox phosphorylation at S303-4 or S379 on TNFα-signaling via TRAF4 and MAPK in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2012; 32:1488-1496.
12. Tickner, J., L. M. Fan, J. Du, D. Meijles, and J-M. Li. Nox2-derived ROS in PPARγ signaling and cell-cycle progression of lung alveolar epithelial cells. Free. Rad. Biol. Med. 2011; 51:763-772.
13. Thakur S., J. Du, S. Hourani, C. Ledent and J-M. Li. Inactivation of adenosine A2A receptor attenuates basal and angiotensin II-induced ROS production by Nox2 in endothelial cells. J. Biol. Chem. 2010; 285:40104-40113.
14. Fan L., L. Teng, and J-M. Li. Knockout of p47phox uncovers a critical role of p40phox in reactive oxygen species production in microvascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2009; 29:1651-1656.
15. Fan L., D. Sawbridge, V. George, L. Teng, A. Bailey, I. Kitchen, and J-M. Li. Chronic cocaine induced Cardiac oxidative stress and MAPK activation: The role of Nox 2 oxidase. J. Pharmacol. Exp. Ther. 2009; 328:99-106.
16. Ribe D., D. Sawbridge, S. Thakur, M. Hussey, C. Ledent, I. Kitchen, S. Hourani, and J-M. Li. Adenosine A2A receptor signalling regulation of cardiac NADPH oxidase activity. Free. Rad. Biol. Med. 2008; 44:1433-1442.
17. Duncan E., S. Walker, V. Ezzat, S. Wheatcroft, J-M. Li, A. Shah, M. Kearney. Accelerated endothelial dysfunction in mild pre-diabetic insulin resistance: the early role of reactive oxygen species. Am. J. Physiol. Endoc. & Metab. 2007; 293:E1131-1139.
18. Li J-M., L.M. Fan, V. T. George, G. Brooks. Nox2 regulates endothelial cell cycle arrest and apoptosis via p21cip1 and p53. Free. Rad. Biol. Med. 2007; 43: 976-986.
19. Li J-M., L.M. Fan, M.R. Christie A. Shah. Acute TNFα signaling via NADPH oxidase in microvascular endothelial cells: Role of p47phox phosphorylation and binding to TRAF4. Mol. Cell. Biology 2005; 25:2320-2330.
20. Noronha, B.T., J-M. Li, S.B. Wheatcroft, A.M. Shah, M.T. Kearney. Inducible nitric oxide synthase has divergent effects on vascular and metabolic function in obesity. Diabetes. 2005; 54:1082-1089.
21. Wheatcroft S.B., A.M. Shah, J-M. Li, E. Duncan, B.T. Noronha, P.A. Crossey, M.T. Kearney. Preserved glucoregulation but attenuation of the vascular actions of insulin in mice heterozygous for knockout of the insulin receptor. Diabetes. 2004; 53:2645-2652.
22. Li, J-M., S. B. Wheatcroft, L. M. Fan, M. T. Kearney and A. M. Shah. Opposing roles of p47phox in basal versus angiotensin II-stimulated alterations in vascular O2.- production, vascular tone and mitogen-activated protein kinase activation. Circulation. 2004; 109:1307-1313.
23. Li, J-M., and A.M. Shah. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. (Invited Review) Am. J Physiol. Regulatory, Integrative and Comparative Physiology. 2004; 287:R1014-R1030.
24. Li J-M., L. M. Fan, A. Shah and G. Brooks. Targeting αvβ3 and α5β1 for gene delivery to proliferating VSMC- synergistic effect of TGF-β1. Am. J. Physiol. Heart Circ. Physiol. 2003; 285:H1123-H1131
25. Byrne, J.A., D. J. Grieve, J. K. Bendall, J-M. Li, C. Gove, J.D. Lambeth, A.C. Cave, and A.M. Shah. Contrasting Role of NADPH oxidase isoform in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Circ. Res. 2003;93:802-804.
26. Li, J-M., and A. M. Shah. Mechanism of endothelial cell NADPH oxidase activation by angiotensin II: Role of the p47phox subunit. J. Biol. Chem. 2003; 278:12094-12100.
27. Li, J-M., and A. M. Shah. ROS generation by non-phagocytic NADPH oxidase: Potential relevance in diabetic nephropathy. (Invited Review) J. Am. Soc. Nephrol. 2003;14: S221-S226.
28. Li, J-M. A.M. Mullen, S. Yun, F. Wientjes, G. Brouns, A.J. Thrasher, J. Rose and A.M. Shah. Essential role of the NADPH oxidase subunit p47phox in endothelial cell superoxide production in response to phorbol ester and tumor necrosis factor-α. Circ. Res. 2002;90:143-150.
29. Li, J-M. and A.M. Shah. Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells. J. Biol. Chem. 2002; 277:19952-19960.
30. Li, J-M., N. P. Gall, D. J. Grieve, M. Y. Chen, and A.M. Shah. Activation of myocardial NADPH oxidase and mitogen activated protein kinases during progression of pressure overload cardiac hypertrophy to failure. Hypertension 2002;40:504-510.
31. Layland, J., J-M. Li, and A.M. Shah. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in isolated cardiac myocytes. J. Physiol. 2002; 540.2:457-467.
32. Li, J-M. A.M. Mullen, and A.M. Shah. Phenotypic properties and characteristics of superoxide production by mouse coronary microvascular endothelial cells. J. Mol. Cell. Cardiol. 2001;33:1119-1131.
33. Li, J-M. and A.M. Shah. Differential NADPH- versus NADH-driven superoxide production by phagocyte-type endothelial cell NADPH oxidase. Cardiovasc. Res. 2001; 52:477-486.
34. Tavernier, B., J-M. Li, M. M. El-Omar, S. Lanone, Z-K. Yang, I. P. Trayer, A. Mebazaa and A. M. Shah. Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J. 2001; 15:294-296.
35. MacCarthy, P. A., D. J. Grieve, J-M. Li, C. Dunster, F. J. Kelly, A. M. Shah. Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: Role of reactive oxygen species and NADPH oxidase. Circulation. 2001; 104:2967-2974.
36. Li, J-M., L. Collins, X. Zhang, K. Gustafsson, and J.W. Fabre. Efficient gene delivery to vascular smooth muscle cells using a non-toxic, synthetic peptide vector system targeted to membrane integrins: a first step toward the gene therapy of chronic rejection. Transplantation. 2000; 70:1616-1624.
37. Poolman, R., J-M. Li, B. Durand, and G. Brooks. Altered expression of cell cycle proteins and prolonged duration of cardiac myocyte hyperplasia in p27KIP1 knockout mice. Circ. Res. 1999; 85:117-127.
38. Eaton, P., J-M. Li, D. J. Hearse, and M. J. Shattock. Formation of 4-hydroxynonenal-modified proteins in the ischemic rat heart. Am. J. Physiol. 1999;276:H935-943.
39. Li, J-M., and G. Brooks. Cell cycle regulatory molecules (cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors) and the cardiovascular system: protential targets for therapy. Eur. Heart J. 1999; 20:406-420.
40. Brooks, G., R. A. Poolman, and J-M. Li. Arresting developments in the cardiac myocyte cell cycle: Role of cyclin-dependent kinase inhibitors. Cardiovasc. Res. 1998; 39:301-311.
41. Burger, D., R. Rezzonico, J-M. Li, C. Modoux, R. A. Pierce, H. G. Welgus, and J. M. Dayer. Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases-1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes. Arthritis & Rheum. 1998; 41(10):1748-1759.
42. Li, J-M., R. Poolman, and G. Brooks. Role of G1 phase cyclins and cyclin dependent kinases during cardiomyocyte hypertrophic growth in rat. Am. J. Physiol. 1998; 275 (Heart Cir. Physiol. 44):H814-H822.
43. Li, J-M., and G. Brooks. Down-regulation of the cyclin dependent kinase inhibitors, p21 and p27, in pressure overload hypertrophy. Am. J. Physiol. 1997; 273 (Heart Circ. Physiol. 42):H1358-H1367.
44. Li, J-M., and G. Brooks. Differential protein expression and subcellular distribution of TGFβ1, β2 and β3 during cardiac hypertrophy. J. Mol. Cell. Cardiol. 1997;29:2213-2224.
45. Brooks, G., R. A. Poolman, C. J. McGill, and J-M. Li. Expression and activities of cyclins and cyclin-dependent kinases in developing rat ventricular myocytes. J. Mol. Cell. Cardiol. 1997;29:2261-2271.
46. Li, J-M., W. Fan, A.C. Horsfall, A.C. Anderson, S. Rigby, E. Larson and P.J.W. Venables. The expression of human endogenous retrovirus-3 in fetal cardiac tissue and antibodies in congenital heart block. Clin. Exp. Immunol. 1996; 104:388-393.
47. Horsfall, A.C., J-M. Li, and R.N. Maini. Placental and fetal cardiac laminin are targets for cross-reacting autoantibodies from mothers of children with congenital heart-block. J. Autoimmunity 1996; 9:561-568.
48. Li, J-M., P. Isler, J-M. Dayer, and D. Burger. Contact-dependent stimulation of monocytic cells and neutrophils by stimulated T cell clones. Immunology 1995; 84:571-76.
49. Li, J-M., A.C. Horsfall, and R.N. Maini. Anti-La (SS-B) but not anti-Ro52 (SS-A) cross-reaction with laminin -a role in the pathogenesis of congenital heart block? Clin. Exp. Immunol. 1995; 99:316-24.
50. Li, J-M., E. Camenzind, B. Meier and W. Rutishauser. Inhospital monitoring after coronary angioplasty. J. Interventional Cardiol. 1994; 7: 229-235.
51. Giroud, D., J-M. Li, P. Urban, B. Meier, and W. Rutishauser. Is the site of myocardial infarction related to the most severe stenosis at prior angiography? Am. J. Cardiol. 1992; 69:729-732.
International patent (Application No: PCTGB2012000725; Publication No: WO/2013/038136) Publication date: 21/03/2013; priority date: 16/09/2011. Inventors: Jian-Mei Li, Brendan Howlin, Daniel Meijles. Title: Bi-aromatic and tri-aromatic compounds as NADPH oxidase 2 (Nox2) inhibitors.