Dr. Salvador Moncada: London, UK
Prof. Moncada was born in Honduras and graduated from Medical School in El Salvador. In 1971 he came to the Royal College of Surgeons in London to do a PhD. There he contributed to the discovery of the inhibition of the enzyme cyclo-oxygenase, and thus of prostaglandin biosynthesis, by aspirin-like drugs and to the elucidation of the mechanism by which these drugs act as analgesic and antiinflammatory agents. In 1975, at The Wellcome Research Laboratories, he was responsible for the discovery of thromboxane synthase, an enzyme in platelets that converts prostaglandin endoperoxides into the vasoconstrictor and platelet-aggregating agent thromboxane A2; he also identified inhibitors of this enzyme. In 1976 he initiated and led the work that resulted in the discovery of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation produced by vascular endothelium. Many of the fundamental discoveries in the area of thromboxane and prostacyclin research were carried out by this group over the following 10 years. His studies have contributed to the understanding of how small doses of aspirin prevent cardiovascular episodes such as myocardial infarction and stroke. In addition, a synthetic analogue of prostacyclin (iloprost) is used clinically to treat primary pulmonary hypertension.
In 1986 Professor Moncada developed a method for the biological detection of the so-called endothelium-derived relaxing factor (EDRF). Using this system, which has become widely accepted as a bioassay for the study of EDRF, he and his group made two observations; firstly, that EDRF was inactivated by superoxide anions (O2- ) but not by other oxygen-derived radicals and secondly, that many of the described putative inhibitors of EDRF act as a result of their redox properties leading to the generation of O2- in solutions. This initial work provided some of the clues for the later identification of the chemical structure of EDRF and helped to clarify the controversy that existed at the time about the possible nature of EDRF and the mechanism of action of its inhibitors.
Professor Moncada and his colleagues demonstrated the release of nitric oxide (NO) from vascular endothelial cells and showed that this release occurred in quantities sufficient to account for the biological actions of EDRF. For this they developed a chemiluminescence detection technique that is now widely used in the field of NO research. Furthermore, they showed that NO is synthesized from the amino acid L-arginine, specifically from its terminal guanidine nitrogen atom(s), by an enzyme (NO synthase) which concomitantly forms L-citrulline. His group first showed that the L-arginine analogue NG-monomethyl-L-arginine (L-NMMA) is an enantiomerically-specific inhibitor of the synthesis of NO in vitro and that inhibition of NO synthesis in vivo leads to hypertension. They thus demonstrated that NO was an endogenous regulator of blood pressure. Prof. Moncada’s group also showed that NO inhibits platelet aggregation and adhesion via elevation of cyclic GMP and that prostacyclin potentiates the anti-aggregatory but not the anti-adhesive properties of EDRF. The L-arginine: NO pathway is now known to be ubiquitous in both mammalian and non-mammalian tissues and the synthesis of NO has been shown to underlie a wide variety of physiological and pathophysiological functions in the cardiovascular, central and peripheral nervous, and immune systems.
In 1989, Prof. Moncada’s group demonstrated that the L-arginine: NO pathway is present in the central nervous system where it acts as a neuro- mediator with many physiological roles. They also found that oestrogens increase the quantities of endothelial and neuronal NO synthases. This is probably one of the mechanisms by which the cardiovascular system adapts itself to the increased load of pregnancy and may explain, at least in part, why premenopausal women are protected against heart disease.
Prof. Moncada and his group later discovered that glucocorticoids inhibit the expression of the inducible NO synthase in vitro. Inhibition by glucocorticoids of the induction of a NO synthase might account for some of the physiological, pharmacological and toxic effects of these compounds. They also found NO to be present in the exhaled air of nor- mal animals and man and they speculated that this may be a physiological excretion which might be augmented in pathological states such as asthma. This has led to a widespread interest in the possible role of NO in this and other inflammatory conditions. Furthermore, measurements of the fraction of exhaled NO constitute a non-invasive marker in patients with asthma for adjustment of their inhaled corticosteroid treatment.
Prof. Moncada’s group cloned the inducible human NO synthase from chondrocytes and was one of the first groups that produced knockout mice for this enzyme. These mice are proving extremely useful in the investigation of the roles played by NO in defence mechanisms of the body and in immunopathology. They later used human tumour cell lines transfected with inducible NO synthase to induce tumours in nude mice and have found that NO might have some tumour-promoting activity through an angiogenic effect.
More recently Prof. Moncada has focused on the role of NO as a regulator of cell respiration. In 1994 he and his group demonstrated that NO, at physiological concentrations, inhibits the mitochondrial enzyme cytochrome c oxidase (complex IV), in competition with oxygen. They also showed in endothelial cells that endogenous NO modulates oxygen consumption under basal and stimulated conditions and that the interaction of NO with cytochrome c oxidase can act as a signalling mechanism that confers cytoprotection. Furthermore, they demonstrated that at low oxygen concentrations this interaction causes the diversion of oxygen to non-mitochondrial oxygen-dependent tar- gets. They went on to characterize the sequence of events that follow inhibition of cytochrome c oxidase by continuous exposure to NO and showed that oxidative stress develops with the subsequent inhibition of other mitochondrial and cytosolic enzymes. This led them to suggest that in this way NO may progress from acting as an important physiological regulator of cell respiration to becoming an agent of cell pathology. Indeed, they showed that NO is a factor in the stabilization of hypoxia-inducible factor in cancer.
Prof. Moncada’s group have shown that inhibition of respiration by exogenous NO leads to mitochondrial membrane hyperpolarization dependent on the utilization of glycolytic ATP by the F1F0-ATPase and other transporters acting in reverse mode. This process occurs in highly glycolytic cells, but not in neurons, which do not invoke glycolysis to maintain ATP concentrations. They further demonstrated that this hyperpolarization correlates with protection against apoptotic cell death.
Most recently, Prof. Moncada and co-workers have investigated the role of endogenous NO in mitochondrial biogenesis; they have shown that NO promotes mitochondriogenesis (and hence oxidative metabolism) and that the inflammatory cytokine tumour necrosis factor (TNF)-alpha downregulates this process in obese animals. Furthermore, they have demonstrated that calorie restriction promotes mitochondriogenesis by inducing the expression of endothelial NO synthase. These findings have implications for novel treatment of diseases of metabolic origin, including type-2 diabetes mellitus and obesity-linked cardio- vascular disorders.
Since 1996 Prof. Moncada has established and directed The Wolfson Institute for Biomedical Research at University College London.