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Molecular physiology of redox signaling in the vascular system and cultured cell models


Vascular endothelial dysfunction is primarily a dysfunction of redox signaling. These processes involve the effect of free radicals, redox-active metals and reducing equivalents on specific proteins that govern cell function. The enzymatic pathways underlying superoxide radical and other reactive oxygen species (ROS) production are yet unclear. A number of evidences, including work from our laboratory, suggest that NAD(P)H oxidase activity is a major source of vascular superoxide. Our data suggest that vascular NAD(P)H oxidase-mediated superoxide production has a signaling role in the early program of the vascular injury repair reaction. However, the enzymatic pathways underlying such NAD(P)H oxidase activity remain controversial. In particular, the extent to which the vascular enzyme resembles that of professional phagocytes is unclear. Other points are also unclear, namely: the physiological role of this(ese) enzyme(s) in vasomotricity and apoptosis, the factors that modulate enzyme activity and the role of reactive nitrogen species, e.g. peroxynitrite in enzyme function. Recently, our laboratory showed that reactive thiol groups have a potential permissive or inhibitory role in enzyme function, in a way unrelated to the intracellular glutathione redox status. It is possible, therefore, that the crucial thiol groups are susceptible to modulation by thiol oxidoreductases, e.g., protein disulfide isomerase, which could, therefore, have an important role in the regulation of the oxidase and consequently of overall redox signaling. Other important question is the possible existence of more than one oxidase, which could interact with NADPH oxidase in such a way to constitute a complex ROS generating system working at the same time as second messengers and as electron transport systems in membranes. These ROS sources interact with specific cellular targets involved in the control of apoptosis, differentiation and proliferation. The overall aim of the project is to further our understanding of the enzymatic pathways and physiological processes related to the production of ROS, particularly superoxide, by the vascular system, as well as its interactions with nitric oxide. The major focus is the characterization of structural and physiological aspects of NAD(P)H oxidase(s) in vascular cells, in particular the role of thiol regulatory proteins and effects of the enzyme(s) in apoptosis, vasomotricity and cell differentiation. Those questions are investigated under the perspective of a role for ROS in the vascular response to injury... (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ARAI, ROBERTO J.; OGATA, FERNANDO T.; BATISTA, WAGNER L.; MASUTANI, HIROSHI; YODOI, JUNJI; DEBBAS, VICTOR; AUGUSTO, OHARA; STERN, ARNOLD; MONTEIRO, HUGO P. Thioredoxin-1 promotes survival in cells exposed to S-nitrosoglutathione: Correlation with reduction of intracellular levels of nitrosothiols and up-regulation of the ERK1/2 MAP Kinases. Toxicology and Applied Pharmacology, v. 233, n. 2, p. 227-237, DEC 1 2008. Web of Science Citations: 23.
SAN MARTIN, ALEJANDRA; FONCEA, ROCIO; LAURINDO, FRANCISCO R.; EBENSPERGER, ROBERTO; GRIENDLING, KATHY K.; LEIGHTON, FEDERICO. Nox1-based NADPH oxidase-derived superoxide is required for VSMC activation by advanced glycation end-products. Free Radical Biology and Medicine, v. 42, n. 11, p. 1671-1679, June 2007.
KRIEGER, M. H.; SANTOS, K. F. R.; SHISHIDO, S. M.; WANSCHEL, A. C. B. A.; ESTRELA, H. F. G.; SANTOS, L.; OLIVEIRA, M. G. DE; FRANCHINI, K. G.; SPADARI-BRATFISCH, R. C.; LAURINDO, F. R. M. Antiatherogenic effects of S-nitroso-N-acetylcysteine in hypercholesterolemic LDL receptor knockout mice. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 14, n. 1, p. 12-20, Feb. 2006.
MONTEIRO‚ H.P.; ROCHA OLIVEIRA‚ C.J.; CURCIO‚ M.F.; MORAES‚ M.S.; ARAI‚ R.J. Tyrosine Phosphorylation in Nitric Oxide-Mediated Signaling Events. Methods in Enzymology, v. 396, p. 350-358, 2005.
MONTEIRO, H. P.; SILVA, E. F.; STERN, A. Nitric oxide: a potential inducer of adhesion-related apoptosis-anoikis. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 10, n. 1, p. 1-10, Feb. 2004.
C.M. PERTRINI; A.A. MIYAKAWA; F.R.M. LAURINDO; J.E. KRIEGER. Nitric oxide regulates angiotensin-I converting enzyme under static conditions but not under shear stress. Brazilian Journal of Medical and Biological Research, v. 36, n. 9, p. 1175-1178, Set. 2003.

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