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Anti-inflammatory function of apolipoprotein A-IV in diabetes mellitus and its effects on reverse cholesterol transport from macrophages: influence of modification by advanced glycation

Grant number: 13/23392-1
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): April 01, 2014
Effective date (End): March 31, 2015
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Marisa Passarelli
Grantee:Ligia Shimabukuro Okuda
Supervisor: Kerry-Anne Rye
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of New South Wales (UNSW), Australia  
Associated to the scholarship:13/02854-7 - Anti-inflammatory role of apolipoprotein A-IV in diabetes mellitus and its impact on macrophage reverse cholesterol transport: influence of advanced glycation, BP.PD


The inverse association between HDL and coronary heart disease is well established by epidemiological studies although recent clinical trials and genetic studies have failed in demonstrating cardiovascular benefits by increasing plasma HDL-cholesterol levels. This may be related to the great heterogeneity of HDL particle in size and composition and to the partial loss of function of this lipoprotein. Recently, HDL proteome has demonstrated a different profile of HDL proteins in cardiovascular disease, namely by a reduced concentration of apoA-IV. As apoA-I, apoA-IV presents anti-inflammatory properties and exerts antiatherogenic roles by different mechanisms. In diabetes mellitus, apoA-I modification by advanced glycation end products (AGE) changes its biological properties and its ability to inhibit inflammation and oxidation and to stimulate cholesterol efflux. We recently demonstrated that advanced glycation primes macrophages for inflammation elicited by calgranulins and lipopolysaccharide (LPS), impairing macrophage cholesterol efflux by diminishing the expression of the HDL receptor, ABCA1. In addition, in the presence of AGE, HDL is not able to prevent the secretion of inflammatory markers by macrophages. Our proposal is to analyze the anti-inflammatory property of apoA-IV in diabetes mellitus especially looking at the influence of advanced glycation and how this impacts macrophage reverse cholesterol transport. For this purpose, apoA-IV will be isolated from well and poorly controlled diabetes mellitus patients and healthy control subjects´ plasma. In addition, recombinant apoA-IV will be produced by E.coli and submitted to in vitro glycation. Mouse peritoneal macrophages and human coronary artery endothelial cells (HCAECs) will be treated with different types of apoA-IV and then exposed to LPS. The conditioned medium will be collected in order to measure the production of inflammatory cytokines and adhesion molecules and to treat naive macrophages previously overloaded with cholesterol and 14C-cholesterol to assess the apoA-I mediated cholesterol efflux. In cells, it will be determined: Inflammatory mediators and NF-kB mRNA and protein levels of HDL receptors (ABCA-1 and ABCG-1). Results will help to elucidate the antiatherogenic role of apo A-IV, how this is disturbed by advanced glycation in diabetes mellitus and how can be ameliorated by adequate glycemic control. (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)
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)
OKUDA, LIGIA SHIMABUKURO; IBORRA, RODRIGO TALLADA; RAMOS, PAULA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA; PICKFORD, RUSSELL; WOODS, TOM; BRIMBLE, MARGARET ANNE; RYE, KERRY-ANNE; PASSARELLI, MARISA. Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages. Mediators of Inflammation, v. 2020, . (13/23392-1, 16/15603-0, 15/21072-5, 13/02854-7, 13/26256-1)
OKUDA, LIGIA S.; PICKFORD, RUSSELL; PATEL, MILI; WOODS, TOM; BRIMBLE, MARGARET; RYE, KERRY-ANNE; PASSARELLI, MARISA. Pyrraline, Argpyrimidine and carboxymethyllysine adducts of advanced glycated apoA-IV do not change the apolipoprotein ability in removing cell cholesterol and inhibiting inflammation in macrophages. MOLECULAR & CELLULAR PROTEOMICS, v. 16, n. 8, p. 1-pg., . (13/02854-7, 13/23392-1)

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