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Advanced glycation end-products and renin-angiotensin system: impact on the development of atherosclerosis in dislipidemic mice

Grant number: 11/04631-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2012
Effective date (End): April 30, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Marisa Passarelli
Grantee:Diego Juvenal Gomes
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Advanced glycation end products (AGE) are independently associated with the development of atherosclerosis. AGE reduce cholesterol efflux from macrophages and enhance the uptake of LDL, leading to lipid accumulation in these cells. Furthermore, AGE stimulate both angiotesinogen and angiotensin II receptor (AT-1) expression and share, together with AT-1, intracellular signalling pathways leading to activation of NF-kB and target genes related to atherogenesis. Therefore, it is likely that atherogenesis induced by AGE might be in part linked to an increased expression of renin-angiotensin system (RAAS) in the arterial wall, what has not been adressed in vivo yet. In this present study, we aim to investigate the effects of intraperitoneal injection of AGE-albumin and treatment with losartan (angiotensin II receptor blocker, ARB) in lipid and AGE (carboximethyllisine, CML) accumulation in the apo E knockout aorta, as well as the expression of angiotensin II, AT-1, AGE recpetor (RAGE) and scavenger receptors that recognize modified LDL (SR-A, CD-36, and LOX-1). Eight-week-old ApoE knockout mice will be fed chow diet and randomly divided into four groups (n=10; each group): C, C+ARB, AGE, and AGE+ARB. Animals will receive one daily intraperitoneal injection (1mg/100uL), during 30 days, of control (C) albumin (Group C and C+ARB) or AGE-albumin (group AGE, and AGE+ARB). Animals in ARB groups will be treated with losartan (100 mg/L water). At the end, plasma total cholesterol, triglycerides, glucose, AGE and anti-CML antibody will be determined. The expression of RAAS, scavenger receptors and RAGE will be determined in the aorta by immunohistochemistry and lipid deposition by Oil Red O. Findings will to elucidade the role of glycation in atherogenesis in vivo and the contribution of RAAS. (AU)

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Scientific publications
(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)
FUSCO, FERNANDA B.; GOMES, DIEGO J.; BISPO, KELY C. S.; TOLEDO, VERONICA P.; BARBEIRO, DENISE F.; CAPELOZZI, VERA L.; FURUKAWA, LUZIA N. S.; VELOSA, ANA P. P.; TEODORO, WALCY R.; HEIMANN, JOEL C.; et al. Low-sodium diet induces atherogenesis regardless of lowering blood pressure in hypertensive hyperlipidemic mice. PLoS One, v. 12, n. 5, . (11/04631-0, 11/16164-7, 13/11084-0, 12/19755-9)
PINTO, PAULA RAMOS; FERRARETTO MOURA ROCCO, DEBORA DIAS; OKUDA, LIGIA SHIMABUKURO; MACHADO-LIMA, ADRIANA; CASTILHO, GABRIELA; DA SILVA, KAROLLINE SANTANA; GOMES, DIEGO JUVENAL; PINTO, RAPHAEL DE SOUZA; IBORRA, RODRIGO TALLADA; FERREIRA, GUILHERME DA SILVA; et al. Aerobic exercise training enhances the in vivo cholesterol trafficking from macrophages to the liver independently of changes in the expression of genes involved in lipid flux in macrophages and aorta. LIPIDS IN HEALTH AND DISEASE, v. 14, . (12/19112-0, 11/04631-0, 12/12088-7, 11/15153-1, 12/04831-1, 12/18724-2, 13/02854-7)
GOMES, DIEGO JUVENAL; VELOSA, ANA PAULA; OKUDA, LIGIA SHIMABUKURO; FUSCO, FERNANDA BUENO; DA SILVA, KAROLINNE SANTANA; PINTO, PAULA RAMOS; NAKANDAKARE, EDNA REGINA; CORREA-GIANNELLA, MARIA LUCIA; WOODS, TOM; BRIMBLE, MARGARET ANNE; et al. Glycated albumin induces lipid infiltration in mice aorta independently of DM and RAS local modulation by inducing lipid peroxidation and inflammation. JOURNAL OF DIABETES AND ITS COMPLICATIONS, v. 30, n. 8, p. 1614-1621, . (13/11084-0, 11/04631-0, 12/19755-9, 11/16164-7, 13/02854-7, 13/23392-1)

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