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Zawartość zarchiwizowana w dniu 2024-05-29

Eicosanoids and Nitric Oxide: Mediators of Cardiovascular, Cerebral & Neoplastic Diseases

Final Report Summary - EICOSANOX (Eicosanoids and Nitric Oxide: Mediators of Cardiovascular, Cerebral & Neoplastic Diseases)

Eicosanoids and nitric oxide (NO) are signalling molecules in many physiological and pathological processes, including severe endemic diseases, e.g. atherosclerosis, myocardial infarction, thrombosis, dementia and cancer. In addition, these inflammatory mediators are involved in many other disorders, e.g. diseases of the respiratory system (asthma), autoimmune disorders, and sequelae after severe trauma. Together, these diseases account for the vast majority of morbidity and mortality cases in Europe, with a major socioeconomic impact.

Due to the wealth of excellent project results, only a few can be briefly described here. Thus, for lysyl oxidase (LOX) enzymes, novel stimulatory factors, including commercial lipase preparations (CLPs) and glycerides, were identified. A particular highlight was the high-resolution crystal structure of the integral membrane protein human LTC4 synthase, a remarkable scientific achievement which has opened novel avenues for drug design. Furthermore, the project characterised gene expression profiles and demonstrated increased messenger RNA (mRNA) levels of 5-LO pathway proteins in human atherosclerotic lesions that were found to correlate with plaque instability; LTA4 hydrolase was identified as a potential drug target. Genes and proteins were characterised, including the identification of gpr17 as a novel leukotriene receptor and potential drug target.

A novel system for production of NO from nitrate and nitrite was elucidated and its surprising physiological effects on the cardiovascular system uncovered. Also, angiotensin II was shown to impair endothelial function by Tyr-phosphorylation of eNOS. The regulation of COX-2 expression in macrophages was described in detail and understanding of this enzyme in tumour development increased significantly.

Cardiovascular side effects of various coxibs were assessed and, importantly, it was found that use of traditional non-steroidal anti-inflammatory drugs (NSAIDs) is also associated with these cardiovascular risks, perhaps with the exception of naproxen. These clinical studies changed the view on NSAID side effects with direct implications for the clinical use of these important drugs. In addition, promising biomarkers for predicting the relative risk of myocardial infarction associated with different NSAIDs were identified.

Because of these achievements, members of the consortium regularly appeared in various European public media, filed 15 patents and created 3 spin-off companies. Clearly, the project increased knowledge of the mechanisms by which eicosanoids and NO trigger and maintain physiological and pathophysiological processes, in both health and disease.

In addition, the project identified new drug targets, improved existing therapies and developed novel drugs and therapeutic strategies. Hence, it seems more than likely that the long-term objectives of EICOSANOX, i.e. to significantly improve the health, and quality of life of the citizens of Europe, will be accomplished.

EICOSANOX was a great success, with scientific progress that reached far beyond project expectations. Thus, the project produced an impressive amount of high-quality science that reached the pinnacle of international prestigious journals, including New Engl J Med, Nature, Mol Cell, Lancet, Nat Chem Biol, Nat Immunol, TiBS, J Clin Invest, J Exp Med, Circulation, J Am Coll Cardiol, Genes Dev, Blood, EMBO J, and Proc Natl Acad Sci USA.