Professor Jian-mei Li

Biography

Dr. Professor Jian-Mei Li is currently working as a Professor of Cardiovascular Biology in the Department of Institute of Caediovascular & Metabolic Research (ICMR), University of Reading , United Kingdom. Patents: 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. Research groups / Centres: Member of: • ICMR • Molecular & Cellular Medicine Group • The British Society for Cardiovascular Research • British Pharmacological Society Fellow of: • Chinese Life Scientists Society in UK (CLSS-UK)

Research Interest

. 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.