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Titlul proiectului: Noi strategii de farmacologie moleculara de reducere a stresului oxidativ si inflamator in celulele peretelui vascular in diabet.

Director de proiect: Dr. Adrian Manea

Rezumatul proiectului

Ateroscleroza accelerată reprezintă una dintre complicațiile vasculare majore ale diabetui zaharat și este responsabila pentru 70-80% din decesele la pacientii cu diabet zaharat în societățile occidentale, inclusiv în România. Stresul oxidativ și inflamator joacă un rol importnant în debutul, progresia, și stabilitatea leziunilor aterosclerotice. Cu toate acestea, mecanismele exacte implicate în dezvoltarea acestei boli nu sunt complet elucidate. Proteine tirozin kinazele, Jak și c-Src sunt traductoare importante ale concentratiei crescute de glucoza, specii reactive de oxigen, și sunt implicate in medierea semnalelor moleculare induse de receptorii pentru produsii finali de glicozilare avansata, citokine, agenți vasoactivi și factori metabolice. În acest context, modularea activităților Jak și c-Src poate reprezenta o noua și importanta strategie farmacologice in vederea atenuarii efectelor patologice induse de stimulii pro-inflamatori, în diabet și complicațiile sale. Utilizand modele experimentale in vitro (culturi de celule endoteliale si musculare netede aortice umane expuse la condiții specifice diabetui zaharat), si modele in vivo - soareci cu diabet zaharat și hipercolesterolemici /hiperglicemici, această propunere are drept scop de a investiga: (1) procesele fundamentale implicate în dezvoltarea placilor ateromatoase în condiții de diabet zaharat și de a investiga rolul axei stress-oxidativ - inflamatie-Jak/c-Src în aterogeneză, (2) elucidarea mecanismelor moleculare implicate în hiperactivitatea NADPH oxidazelor și inducerea stresului oxidativ în celulele peretelui vascular în diabet; (3) investigarea potențialului anti-oxidant și anti-inflamator de catre diferite clase de medicamente de ultima generatie (inhibitori farmacologici ale Jak și c-Src). Transferul rezultatelor obținute prin aceste studii în clinică pot contribui la definirea unor noi strategii terapeutice pentru corectarea factorilor de risc cardiovascular și pentru a preveni aparitia complicațiilor si eventimentelor cardiovasculare majore in populația diabetică.

Publicatii

Articole ISI peer-review:

Manea A, Manea SA, Todirita A, Albulescu IC, Raicu M, Sasson S, Simionescu M. High glucose-increased expression and activation of NADPH oxidase in human vascular smooth muscle cells is mediated by 4-hydroxynonenal-activated PPARα and PPARβ/δ. Cell Tissue Res. 2015; DOI: 10.1007/s00441-015-2120-0.
Manea A, Manea SA, Florea IC, Luca CM, Raicu M. Positive regulation of NADPH oxidase 5 by proinflammatory-related mechanisms in human aortic smooth muscle cells. Free Radic Biol Med. 2012 May 1;52(9):1497-507.
Manea A, Simionescu M. Nox enzymes and oxidative stress in atherosclerosis. Front Biosci (Schol Ed). 2012 Jan 1;4:651-70.
Fenyo IM, Florea IC, Raicu M, Manea A. Tyrphostin AG490 reduces NAPDH oxidase activity and expression in the aorta of hypercholesterolemic apolipoprotein E-deficient mice. Vascul Pharmacol. 2011 Mar-Jun;54(3-6):100-6.
Manea A. NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res. 2010 Dec;342(3):325-39.

Articole peer-review indexate in baza de date internationala

Fenyo IM, Manea A, Manea SA. The caffeic acid derivate WP1066 down-regulates NADPH oxidase-derived reactive oxygen species in the aorta of atherosclerotic apolipoprotein-E deficient mice. Annals of RSCB, 2013, XVIII (1), 50-55.
Manea A,Fenyo IM, Florea IC, Raicu M. Distinct roles of NADPH oxidase isoforms in high glucose-induced reactive oxygen species formation in human aortic smooth muscle cells. Annals of RSCB, 2010, XV (2), 26-31.

Capitole aparute in carti:

- Manea A. Vascular biology of reactive oxygen species and NADPH oxidases: role in atherogenesis. Atherogenesis 2012, Chapter 20, 425-446, ISBN 978-953-307-992-9. Book edited by: Dr. Sampath Parthasarathy PhD, MBA, The Ohio State University, USA.

Project code: TE_1

Project title: Novel molecular pharmacology strategies for reduction of oxidative stress and inflammation in the vascular wall cells in diabetes.

Project director: Dr. Adrian Manea

Summary of the project

Accelerated atherosclerosis represents the major vascular complication of diabetes mellitus and is responsible for 70-80% of deaths in diabetic patients in western societies, including Romania. Oxidative stress and inflammation play a key role in the onset, progression, and stability of atherosclerotic lesions. However, the precise mechanisms implicated in the development of this disorder are not completely elucidated. Protein tyrosine kinases, Jak and c-Src are important transducers of high glucose concentration, reactive oxygen species, and mediate the signals from the receptors for advanced glycation end products, cytokines, vasoactive agents, and metabolic factors. In this context, modulation of the Jak and c-Src activities may represent a novel and important pharmacological strategy to attenuate the pathological effects induced by pro-inflammatory stimuli in diabetes and its complications. Using in vitro experimental models (cultured human aortic endothelial cells and smooth muscle cells exposed to diabetic conditions), and in vivo models – diabetic and hypercholesterolemic/diabetic mice, this proposal aims to investigate: (1) the fundamental processes implicated in the development atheromatous plaque in diabetic conditions and to investigate the role of the oxidative stress-inflammation-Jak/c-Src axis in atherogenesis; (2) elucidation of the molecular mechanisms involved in the hyperactivity of NADPH oxidases and the consequent induction of oxidative stress in the vascular cells in diabetes; (3) investigation of antioxidant and anti-inflammatory potential of several innovative drugs (pharmacological inhibitors of Jak and c-Src). The translation into clinic of the results produced by these studies will enhance defining new therapeutic strategies to correct the cardiovascular risk factors and to prevent the escalation of cardiovascular diseases and their downstream complications in the diabetic population.

Publications

Peer-review ISI articles:

Manea A, Manea SA, Todirita A, Albulescu IC, Raicu M, Sasson S, Simionescu M. High glucose-increased expression and activation of NADPH oxidase in human vascular smooth muscle cells is mediated by 4-hydroxynonenal-activated PPARα and PPARβ/δ. Cell Tissue Res. 2015; DOI: 10.1007/s00441-015-2120-0.
Manea A, Manea SA, Florea IC, Luca CM, Raicu M. Positive regulation of NADPH oxidase 5 by proinflammatory-related mechanisms in human aortic smooth muscle cells. Free Radic Biol Med. 2012 May 1;52(9):1497-507.
Manea A, Simionescu M. Nox enzymes and oxidative stress in atherosclerosis. Front Biosci (Schol Ed). 2012 Jan 1;4:651-70.
Fenyo IM, Florea IC, Raicu M, Manea A. Tyrphostin AG490 reduces NAPDH oxidase activity and expression in the aorta of hypercholesterolemic apolipoprotein E-deficient mice. Vascul Pharmacol. 2011 Mar-Jun;54(3-6):100-6.
Manea A. NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res. 2010 Dec;342(3):325-39.

Peer-review articles indexed in international database

Fenyo IM, Manea A, Manea SA. The caffeic acid derivate WP1066 down-regulates NADPH oxidase-derived reactive oxygen species in the aorta of atherosclerotic apolipoprotein-E deficient mice. Annals of RSCB, 2013, XVIII (1), 50-55.
Manea A,Fenyo IM, Florea IC, Raicu M. Distinct roles of NADPH oxidase isoforms in high glucose-induced reactive oxygen species formation in human aortic smooth muscle cells. Annals of RSCB, 2010, XV (2), 26-31.

Book chapters: