Influence of modified albumin from Diabetes mellitus in the differential expression of genes and lipid flux in macrophages: the role of reactive oxygen species, inflammatory markers and endoplasmic reticulum stress

• Grant number: 09/53869-9
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2010
• End date: October 31, 2012
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Marisa Passarelli
• Grantee: Marisa Passarelli
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Advanced glycation end products (AGE) are independently related to the development of atherosclerosis in diabetes mellitus (DM). By reducing the HDL half-life in plasma and the expression of ABCA-1 and ABCG-1 receptors and by increasing the expression of scavenger receptors and inflammatory markers, AGEs disturb the macrophage reverse cholesterol transport thus contributing to macrophage cholesterol accumulation. These events are related to the AGE-induced reactive oxygen species (ROS) generation, which can be prevented by anti-AGE compounds and chemical inhibitors of NADPH oxidase. In macrophages, the transcriptional activity of the ABCG-1 gene is down regulated by AGE-albumin; on the other hand, the reduced expression of ABCA-1 protein is not related to changes in gene transcription and mRNA levels. Thus, it is reasonable to postulate that post translational degradation, induced by redox imbalance and cell cholesterol accumulation, could contribute to the reduction in ABCA-1 expression elicited by AGE-albumin. Considering that albumin is the major circulating protein modified by glycation in DM and is used as a parameter of tight glycemic control, the objective of this study is to analyze in macrophages the role of in vivo and in vitro advanced glycated albumin in: 1) the differential expression of genes involved in lipid metabolism and inflammation; 2) ROS generation; 3) expression of endoplasmic reticulum stress markers and proteasomal degradation and 4) HDL-mediated lipid efflux. Macrophages will be treated with control albumin, isolated from healthy individual's serum or AGE-albumin, isolated from poorly controlled DM patients or modified in vitro by oxoaldehyde treatment. A detailed analysis of the effect of AGE in macrophage lipid metabolism and its relationship with inflammation and proteasomal degradation contribute to the comprehension of cell signaling involved in ABCA-1 regulation that ultimately brings on the development of atherosclerosis. (AU)

Scientific publications

(5)

(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)

OKUDA, LIGIA S.; CASTILHO, GABRIELA; ROCCO, DEBORA D. F. M.; NAKANDAKARE, EDNA R.; CATANOZI, SERGIO; PASSARELLI, MARISA. Advanced glycated albumin impairs HDL anti-inflammatory activity and primes macrophages for inflammatory response that reduces reverse cholesterol transport. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1821, n. 12, p. 1485-1492, DEC 2012. (09/53869-9)

MACHADO-LIMA, ADRIANA; IBORRA, RODRIGO T.; PINTO, RAPHAEL S.; SARTORI, CAMILA H.; OLIVEIRA, ERIKA R.; NAKANDAKARE, EDNA R.; STEFANO, JOSE T.; GIANNELLA-NETO, DANIEL; CORREA-GIANNELLA, MARIA LUCIA C.; PASSARELLI, MARISA. Advanced glycated albumin isolated from poorly controlled type 1 diabetes mellitus patients alters macrophage gene expression impairing ABCA-1-mediated reverse cholesterol transport. DIABETES-METABOLISM RESEARCH AND REVIEWS, v. 29, n. 1, p. 66-76, JAN 2013. (09/53869-9, 07/59710-6)

CASTILHO, GABRIELA; OKUDA, LIGIA S.; PINTO, RAPHAEL S.; IBORRA, RODGIRO T.; NAKANDAKARE, EDNA R.; SANTOS, CELIO X.; LAURINDO, FRANCISCO R.; PASSARELLI, MARISA. ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - Reversal by a chemical chaperone. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, v. 44, n. 7, p. 1078-1086, JUL 2012. (09/53869-9)

IBORRA, RODRIGO T.; MACHADO-LIMA, ADRIANA; CASTILHO, GABRIELA; NUNES, VALERIA S.; ABDALLA, DULCINEIA S. P.; NAKANDAKARE, EDNA R.; PASSARELLI, MARISA. Advanced Glycation in macrophages induces intracellular accumulation of 7-ketocholesterol and total sterols by decreasing the expression of ABCA-1 and ABCG-1. LIPIDS IN HEALTH AND DISEASE, v. 10, SEP 29 2011. (09/53869-9, 07/59710-6)

MACHADO-LIMA, ADRIANA; IBORRA, RODRIGO T.; PINTO, RAPHAEL S.; CASTILHO, GABRIELA; SARTORI, CAMILA H.; OLIVEIRA, ERIKA R.; OKUDA, LIGIA S.; NAKANDAKARE, EDNA R.; GIANNELLA-NETO, DANIEL; MACHADO, UBIRATAN F.; et al. In Type 2 Diabetes Mellitus Glycated Albumin Alters Macrophage Gene Expression Impairing ABCA1-Mediated Cholesterol Efflux. Journal of Cellular Physiology, v. 230, n. 6, p. 1250-1257, JUN 2015. (09/53869-9, 07/59710-6)